The granulin gene family: from cancer to dementia

DOI 10.1002/bies.200900086 My favorite molecule

The granulin gene family: from cancerto dementiaAndrew Bateman* and Hugh P. J. Bennett

Endocrine Research Laboratory, McGill University Health Centre, Royal Victoria Hospital, Montreal, Canada

The growth factor progranulin (PGRN) regulates celldivision, survival, and migration. PGRN is an extracel-lular glycoprotein bearing multiple copies of thecysteine-rich granulin motif. With PGRN family membersin plants and slime mold, it represents one of the mostancient of the extracellular regulatory proteins still extantin modern animals. PRGN has multiple biological roles.It contributes to the regulation of early embryogenesis,to adult tissue repair and inflammation. Elevated PGRNlevels often occur in cancers, and PGRN immunotherapyinhibits the growth of hepatic cancer xenografts inmice. Recent studies have demonstrated roles for PGRNin neurobiology. An autosomal dominant mutation inGRN, the gene for PGRN, leads to neuronal atrophy inthe frontal and temporal lobes, resulting in the diseasefrontotemporal lobar dementia. In this review we willdiscuss current knowledge of the multifaceted biologyof PGRN.

Keywords: carcinogenesis; evolution; frontotemporal lobar

dementia; inflammation; wounds

Introduction

Our laboratories began to investigate the function of the

granulins (GRNs) while looking for peptides of the innate host

response. While purifying members of the defensin family of

anti-microbial peptides from extracts of human leukocytes,

using a protocol we devised to screen for fractions containing

cysteine-rich peptides, the GRNswere identified in minor side

fractions.(1) Members of the GRN family were also shown to

be significant components in extracts of carpmyeloid tissue.(2)

Sequence analysis of human and carp GRNs revealed a

unique 12-cysteine motif consisting of four pairs of cysteines

flanked by two single cysteines at the amino and carboxyl

termini (Fig. 1A). All cysteines were found to be fully crossed-

linked to form six disulfide bridges. Two-dimensional nuclear

magnetic resonance analysis of purified carp GRN-1 revealed

that the peptide backbone adopts a unique conformation of a

parallel stack of beta-hairpins in the form of a left-handed

*Correspondence to: A. Bateman, Endocrine Research Laboratory, McGill

University Health Centre, Royal Victoria Hospital, 687 Pine Ave West,

Montreal, Canada H3A1A1.

E-mail: [email protected]

BioEssays 31:1245–1254, � 2009 Wiley Periodicals, Inc.

helix.(3) Recombinant mammalian GRN modules show a

similar, but less rigid structure(4) (Fig. 1B). Subsequent work

showed that the mammalian GRN peptides were fragments

of a larger protein, progranulin (PGRN), bearing seven and

one-half GRN repeats (Fig. 1A). While both PGRN and its

constituent GRN peptides have biological activity, most

research has focused on the function of the larger PGRN

protein.

Initially the function of the GRNs was obscure, and our

continued interest in them was based more on the concept

that their unusual chemical structures strongly suggested that

they would prove biologically interesting, than on a clear idea

of function. Slowly work from a number of groups including our

own began to elucidate tentative roles and about 10 years ago

we wrote a review called, optimistically, ‘‘Granulins: the

structure and function of an emerging family of growth

factors.’’(5) In the intervening years, members of the GRN

gene family (GRN) have indeed emerged as significant

players in the extracellular regulation of cell function, although

often in surprising contexts that we had not predicted 10 years

ago. We know now, for example, that the human family

member PGRN is critical in maintaining neuronal survival,

since mutations of the GRN gene lead to cell death in the

frontal and temporal lobes of the brain.(6,7) The role of PGRN

in cancer has been repeatedly demonstrated.(8–26) PGRN has

been invoked in early embryogenesis,(27) wound repair, and

inflammation.(28–30) These are diverse roles, extending from

control of embryonic development during the first days of life

to the survival of long-lived post-mitotic neurons of the adult

brain. In this article we wish to identify unifying themes in the

biology of PGRN and other members of the GRN family that

would help rationalize this complexity.

Evolutionary origins and structure

The unique nature of the 12-cysteine GRN motif makes

unambiguous identification of homologous structures possible.

AGRNmotif is found at the carboxyl terminus of the cathepsin

K family of cysteine proteases found in numerousmembers of

the plant kingdom whose expression is up-regulated by

environmental stressors(31) (Fig. 1A). A form of GRN is found

in the slime mold Dictyostelium discoideum,(32) a social

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My favorite molecule A. Bateman and H. P. J. Bennett

amoeba that is a modern representative of a primordial

organism that is thought to have predated the divergence of

the plant and animal kingdoms. Fungi do not have a GRN

gene. In fish, andmany invertebrate organisms, multipleGRN

Figure 1. The structure of PGRN. A: A comparison of GRN family mem

The circles represent the complete GRN modules of 12 cysteines, while

GRNs are always found at the carboxyl terminus of a cysteine protease.B:

dimensional nuclear magnetic resonance.(4) The two images are identical b

(yellow) form an axial ‘‘rod’’ through the center of themolecule. The beta-str

is violet, oxygen atoms are red, and nitrogen atoms are blue (from NCB

1246

genes are found, whereas mammals possess only one known

member of the GRN gene family. The zebrafish genome, for

example, harbors four GRN genes.(33) zPGRN-A and

zPGRN-B are co-orthologs of the human gene bearing

bers in humans, zebrafish, the slime mold Dictyostelium, and plants.

semi-circles are partial GRN domains of only six cysteines. The plant

The three-dimensional structure of humanGRN-A determined by two-

ut turned approximately 908 in the vertical plane. The disulfide bridgesands are represented by the broad gold arrows. The peptide backbone

I structure database MMDB: 63884 viewed using Cn3D).


A. Bateman and H. P. J. Bennett My favorite molecule

multiple copies of the GRN motif (Fig. 1A). Two smaller forms

(zPGRN-1 and zPGRN-2) are also present (Fig. 1A). Syntenic

conservation of gene location shows that zPGRN-A is the

ortholog of mammalian GRN. Why only one family member

was retained in mammals and other land vertebrates is not

known.

The phylogenetic distribution of the GRN motif suggests

that it evolved only once about 1.5 billion years ago. Has it

always functioned as a signaling factor? The appearance of

complex life forms was concomitant with the evolution of a

multiplicity of cell signaling and cell-cell adhesion proteins

responsible for the complexity and diversity of multicellular

organisms. The sponge Oscarella carmela has a simple

branching body plan but surprisingly has nearly all the

classical growth factor signaling mechanisms including

the Wnt, Hedgehog, and TGF-beta pathways.(34) In contrast,

Monosiga brevicollis, an example of the Choanoflagellates,

which are the closest known unicellular relatives of metazo-

ans, lacks all these critical pathways.(35) However, GRN

genes are found in O. carmela (EC372216), M. brevicollis

(XP_001748993), and D. discoideum (XP_638956), suggest-

ing that the GRN signaling system evolved before most other

contemporary growth factor pathways.

The mammalian GRN gene encodes a multifunctional

secreted glycoprotein with tandem repeats of cysteine-rich

GRN modules(1,36–39) (Fig. 1A). It is known synonymously as

PGRN,(8) granulin-epithelin precursor (GEP),(40) proepithe-

lin,(38) PC cell-derived growth factor (PCDGF),(10) acrogra-

nin,(39) and epithelial transforming growth factor (TGFe).(41)

This rather dense nomenclature for a single gene is revealing

since it captures many of the essential features of the biology

of PGRN. TheGRN nomenclature emphasizes its association

with granulocytes and the cells of the innate immune

system, while the epithelin nomenclature emphasizes its

association with epithelial cells. The PCDGF and TGFe

designations emphasize the functional aspects of the protein

as a growth modulator, while acrogranin (from acrosome, a

compartment of the sperm head) brings out the likely roles of

PGRN in reproduction and early development.

Tissue remodeling and development

PGRN is often expressed under conditions of tissue

remodeling where cells are dividing and actively migrating.

For adult epithelia it is abundant in regions that are

rapidly turning-over, notably in the intestinal deep crypt and

epidermal keratinocytes.(42) Other less mitotically active

epithelia usually express PGRNat far lower levels. Fibroblasts

and endothelial cells, which are normally mitotically quies-

cent, show corresponding low levels of PGRN.(43) However,

these cells can rapidly deploy very active tissue remodeling

programs of increased proliferation and migration following


wounding, for example. As they do so, their expression of

PGRN increases dramatically.(28) The increased expression

of PGRN in wounds is likely to contribute to the repair

process,(28) since adding PGRN to skin wounds in mice

increases the number of fibroblasts and capillaries that enter

the wounds in the early stages of healing.(28) In tissue culture

PGRN stimulated the proliferation and migration through

collagen of dermal fibroblasts and endothelial cells, recapi-

tulating the effects that were observed in the intact

wounds.(28) The actions of PGRN in injury extend to regulating

inflammation, since PGRN is a potent inhibitor of the

inflammatory cytokine tumor necrosis factor-a (TNF-a).(29,30)

Tumors exhibit pathologically disordered tissue remodeling

and PGRN expression is often highly elevated in cancers of

many types including carcinomas,(11,22,44–47) gliomas,(26)

multiple myelomas,(13) and uterine smooth muscle sarco-

mas.(12) In most cases there is a relationship between

the cancer progression and the expression of PGRN, the

higher-grade tumors being more likely to express elevated

PGRN.

PGRN is intimately involved in early embryogenesis and,

importantly, shows specificity of both expression and effect. In

the blastocyst (the fluid-filled form of the embryo prior to

implantation into the uterus), PGRN immunoreactivity is

located in the trophoblast,(48) the outermost shell of cells

around the inner cell mass that expand after implantation to

create the fetal compartment of the placenta. PGRN becomes

detectable in the inner cell mass only after the conceptus has

attached to the uterus.(49) This is consistent with biological

studies in which PGRN was found to stimulate cavitation, the

process whereby the solid ball of cells of the morula becomes

the fluid-filled blastocyst, and shown to have growth-

promoting activity on trophoblasts, but not the inner cell

mass.(48,49) In addition, PGRN stimulates the hatching,

adhesion, and outgrowth of the blastocyst in experimental

models of implantation.(48) PGRN continues to be expressed

in the placenta after implantation(50) and in the embryo,

particularly in the epidermis and developing nervous

system,(51) which may be significant given the recent

discovery of the role of PGRN in neurodegenerative diseases.

Progranulin and neurodegenerativediseases

Although the relationship between PGRN expression and

tissue remodeling is compelling, there are cases where this

evidently does not apply, perhaps the most obvious being in

the post-mitotic cells of the brain and spinal cord, many of

which express PGRN very strongly,(42,51) but are neither

proliferating nor migrating. Recent evidence, mostly from the

genetics of neurological disease, reveals that PGRN protects

neurons from premature death. Mutation of a single copy of

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Figure 2. Different facets of the biological activity of PGRN. A: The partial loss of PGRN causes severe neurodegeneration. The images show

the gross appearance of the brain from a patient carrying a mutation in the PGRN gene (IVS709-2A4G). Note the extensive asymmetric

degeneration with temporal atrophy on the left (L) being more extensive than on the right (R).(99) B: Elevated PGRN levels stimulate proliferation

and tumorigenesis. In murine embryo fibroblasts two growth factors are required to complete the cell cycle, a competence growth factor such as

PDGF and a progression growth factor such as IGF-I. PGRN stimulates cell division but, unlike the classic growth factors, it does so

independently and does not require priming with a competence factor.(16) C: Athymic nude mice were injected subcutaneously with SW13

cells that are normally not tumorigenic in vivo (lower panel), and SW13 cells that over-express PGRN (upper panel). The SW13/PGRN cells

formed large tumors.(8) D: The activity of PGRN is regulated by proteolytic enzymes. In the upper panel (1) PGRN binds SLPI; this prevents the

cleavage of PGRN by neutrophil-derived proteases such as neutrophil elastase (NE) and proteinase-3. The intact PGRN inhibits the activation of

neutrophils by TNF-a and is therefore anti-inflammatory. In the lower panel (2) there is insufficient SLPI to protect PGRN from elastase digestion

and PGRN is broken down to its 6 kDaGRN fragments. The fragments no longer regulate the activity of TNF-a, but instead stimulate the secretion

of interleukin-8, and may therefore be pro-inflammatory.(29,30)


the humanGRN gene results in neuronal atrophy of the frontal

and anterior temporal lobes (frontotemporal lobar degenera-

tion, FTLD)(6,7) (Fig. 2A).

Clinically, this manifests as a disease called frontotemporal

dementia (FTD). FTD is often a familial disease, and typically

appears at a relatively young age, being the second most

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common dementia for people under 60 years. The frontal and

temporal lobes have key roles in regulating behavior, empathy,

and social understanding as well as language and this is

reflected in the initial clinical presentation of the disease.

Generally speaking, three variants of FTD are recog-

nized,(52,53) a behavioral variant (bvFTD), and two forms that



are associated with language problems, namely progressive

non-fluent aphasia, which is characterized by loss in the ability

to produce speech, with the individuals eventually becoming

effectively mute, and semantic dementia, in which patients

retain the ability to speak but in an increasingly disorganized

and meaningless manner as the disease worsens. GRN

mutations are often associated with bvFTD, but many instances

of language-deficit FTD linked to GRN mutations have been

reported.(54) FTD may be accompanied by motor neuron

disease, although this is rare in individuals with mutant GRN.

FTD is genetically heterogeneous. Other mutations in

addition to GRN cause FTD, most notably the microtubule-

associated protein tau (MAPT),(55) and, more rarely, chromatin-

modifying protein 2B (CHMP2B)(56) and the valosin-containing

protein (VCP).(57) MAPT was the first FTD gene to be

identified, and maps in remarkably close proximity to GRN on

chromosome 17q21.3.(6,7) Presently the Alzheimer Disease

and Frontotemporal Dementia Mutation Database (http://

www.molgen.ua.ac.be/FTDMutations/) records 66 distinct

GRN mutations.(58) Most, if not all the GRN-dependent FTDs

result from a decrease in the amount of PGRN expressed or

secreted, rather than an acquired toxic effect of mutant

protein. Many of these mutations lead to nonsense-mediated

mRNA decay, a process that eliminates the mutant transcripts

and therefore lowers the expression level of PGRN mRNA by

50%.(59) Other mutants may affect the translated protein, for

example, by changing one of the cysteines to another residue

and therefore disturbing disulfide bridge formation, or by

impeding secretion throughmutations of the signal peptide.(60,61)

Insufficient production of PGRN protein as the underlying cause

of disease was confirmed with the identification of FTD

associated with allelic loss of the entire GRN locus.(62)

Although neuronal death is the hallmark of FTLD, theGRN-

and MAPT-dependent phenotypes are strikingly different at

the cellular level. In the GRN-linked condition, the neurons

accumulate cytoplasmic and nuclear inclusions that stain

strongly for ubiquitin and phosphorylated fragments of a

protein called TAR DNA-binding protein 43 (TDP-43).(63,64)

Ubiquitin inclusions are rarely found when FTLD is due to

mutantMAPT, instead the affected neurons display aggrega-

tions of the tau protein, identifying this form of FTLD as a

tauopathy along with other dementias such as Alzheimer’s

disease.(65) Thus far, allGRN-linked forms of FTLD examined

exhibit ubiquitin inclusions. However, inclusions occur in

cases of FTLD that do not arise from mutant GRN. Moreover,

the ubiquitin/TDP-43 inclusions occur in other neurodegen-

erative diseases, such as amyotrophic lateral sclerosis (ALS),

where there is no strong link with GRN mutations.(66)

Given the complex histopathological relationship between

GRN mutations and ubiquitin/TDP-43 inclusions, are there

any functional relationships between PGRN and TDP-43?

The ubiquitin/TDP-43 inclusions do not contain PGRN,(67)

and therefore the direct seeding of ubiquitin inclusions by


PGRN is highly unlikely. When PGRN mRNA levels were

depleted in cell culture, TDP-43 underwent a partial caspase-

dependent proteolysis.(68) The fragmentation of TDP-43

appears to be an initial step in the formation of ubiquitin/

TDP-43 inclusions, although it should be pointed out that

other investigators found no alteration in TDP-43 localization

or stability following depletion of PGRNmRNA.(61) The 25 kDa

carboxyl-terminal fragment of TDP-43 accumulates in

neurodegenerative tissue, and, when over-expressed in cells,

it was phosphorylated, ubiquitinated, and cytotoxic.(69,70)

Among its several functions, TDP-43 is a specific mRNA-

binding protein for human neurofilament mRNA,(71) and may

be involved in the response to neuronal injury since its levels

increased and it was translocated from the nucleus to the

cytoplasm in injured motor neurons.(72) As TDP-43 increased

in the injured neurons, the cytoplasmic levels of PGRN

dropped in parallel.(72) Assuming that neuronal PGRN levels

also decrease after injury in the brain, the depletion of the

remaining 50% normal PGRN in GRN-mutant carriers

following cerebral stress or trauma may on occasion bring

neuronal PGRN to very low levels compared to non-carriers.

The functional roles of PGRN in neurons and neurode-

generation are only beginning to be explored. PGRN is

neurotrophic for cortical and spinal cord neurons,(73) which

may be relevant in the loss of cortical neurons in FTD;

however, other factors are likely to be at work. Not everyone

with a GRN mutant develops FTD, and some carriers of

pathological variants ofGRN have lived well into their 70s and

beyond with no apparent loss of cognitive function.(59) This

would suggest that there are important biological modifiers of

GRN pathological outcome, but little if anything is known of

what these may be.

In other cell types, PGRN is a potent extracellular anti-

apoptotic factor(16,21,74) and if this is true also for neurons, the

loss of half the normal level of PGRN may sensitize the

affected neurons to a range of traumatic shocks. Similarly,

PGRN has roles in peripheral inflammation.(29,30) The

equivalent neuroinflammatory cells in the brain, the microglia,

express PGRN very strongly in diseased tissue, and an

inflammatory contribution from PGRN to the disease has

been hypothesized.(75) Although PGRN is widely distributed,

the pathology due to GRN mutations is highly restricted.

PGRN is expressed in many neurons outside the cerebral

cortex,(42) but these appear to be far less affected by GRN

mutations.Why the cells of the frontal and temporal cortex are

so much more sensitive to loss of PGRN than others is not

known. The lack of a direct causative influence in other

neurodegenerative diseases does not exclude more subtle

roles. For instance, genetic variants of GRN may be disease

modifiers in ALS,(76) although other investigators have not

been able to reproduce this correlation.(66)

PGRN has other functions in the brain. The male

hypothalamus undergoes a default female developmental

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program until late in embryonic development when it is

masculinized by the actions of circulating androgens. GRN

mRNA was identified as one of the transcripts that were most

strongly up-regulated by androgens in neonatal mouse

hypothalami and in a series of elegant experiments by Suzuki

et al.(77) it was shown that depletion of PGRN blunts many of

the normal masculine reproductive behaviors, particularly

ejaculation.(78,79) Abrogation of the GRN gene in male mice

showed unusual levels of anxiety, which were attributed at

least in part to decreased expression of the serotonin receptor

5HT1A.(79) These findings coupled with the expression of

PGRN in many regions of the embryonic mouse brain(51) hint

at yet further roles for PGRN in brain development.

Intriguingly, comparative studies also support a key neuronal

role for PGRN, since a PGRN-like protein is evident in the

nerve cells of an annelid ragworm, whose last common

ancestor with vertebrates presumably dates very early in

animal evolution.(80)

Progranulin as a somatic growth factor

PGRN is a double-edged sword. Of equal importance to the

problems that accrue when PGRN levels are low is what

happens to cells with increased exposure to PGRN. Elevated

PGRN stimulates proliferation,(8–10,15,16,28,40) survival,(9,21,74)

and motility(9,24,28) of epithelia, fibroblasts, and endothelia.

PGRN activates typical growth factor signal transduction

pathways such as the phosphorylation of shc and p44/42

mitogen-activated protein kinase (p44/42MAPK) in the

extracellular regulated kinase (ERK) pathway as well as

phosphatidylinositol 3-kinase (PI3K), protein kinase B/AKT,

and the p70S6 kinase in the PI3K pathway.(9,15,16) PGRN

promotes tyrosine phosphorylation of focal adhesion kinase

(FAK),(9) which is a cytoplasmic tyrosine kinase in the

signaling pathways associated with clustered integrins.(81)

FAK provides a link between integrin and growth factor

signaling since it is required for epidermal growth factor (EGF)

and platelet-derived growth factor (PDGF) to promote cell

motility.(82) In bladder cancer cells where PGRN is a strong

motogen but a poor mitogen, PGRN promoted the association

of FAK with paxillin and p44/42MAPK,(24) suggesting, at the

very least, a cellular link between PGRN and extracellular

matrix (ECM) signaling machinery.

To appreciate how the growth factor-like properties of

PGRN differ from those of conventional growth factors, it is

necessary to revisit some of the fundamentals of growth factor

biology. In serum-free medium, normal fibroblasts require two

distinct growth factor signals to progress through the

complete cell cycle.(83) One growth factor, the competence

factor, prepares the cell to pass into the S-phase where DNA

synthesis occurs. The second growth factor, the progression

factor, then drives the cell through the S-phase and into the

1250

M-phase, where cell division takes place. PGRN, unlike

classic growth factors, is simultaneously both a competence

and progression factor, that is, it successfully stimulates

the completion of both S- and M-phase without assistance

from other growth factors.

In murine embryonic fibroblasts, the dominant progression

signal is provided through the insulin-like growth factor-I

receptor (IGFI-R).(83) Disrupting this receptor prevents mouse

embryo fibroblasts from completing the cell cycle not only

in response to IGF-I, the progression factor, but also to

competence factors such as PDGFor EGF.(84) PGRN, however,

circumvented the requirement for the IGFI-R-mediated signal

and supported the traverse of both the S- and M-phase,

allowing the IGFI-R-deficient cells to complete the cell cycle in

serum-free medium(16) (Fig. 2B). PGRN is the only extra-

cellular protein known to do this and appears to achieve this

unusual feat because of the kinetics of its signal transduction

response.(16) Growth factors such as PDGF or EGF elicit

relatively transient signaling responses in IGFI-R-deficient

cells, whereas the PGRN response is considerably more

prolonged.(16) Whether this is due to events at the level of

PGRN receptor-ligand interactions, or to PGRN eliciting

weaker downstream counter-regulatory effects responsible

for turning off the ERK signal after stimulation is unclear.

Frustratingly, identifying the receptors or other PGRN-binding

proteins in cell membranes has proven elusive, making it very

difficult to address questions of this kind.

Progranulin in cancer

Signaling does not prove function. Evidence that PGRN is a

functional growth factor came from work on cancer. Initially

PGRN was found to be an autocrine growth stimulus for an

aggressive murine teratoma.(10) Reducing PGRN mRNA

expression greatly reduced tumor formation by the teratoma

cells,(14) as well as in breast cancer,(17) liver cancer,(46) and

squamous esophageal cancer(18) cell lines in vivo. Clearly

therefore PGRN is required for these cells to be tumorigenic.

To demonstrate whether PGRN is not only necessary for tumor

growth but also actively confers malignancy, it was over-

expressed in a cancer cell line (SW13 adenocarcinoma cells)

that is normally weakly tumor-forming. The PGRN over-

expressing cells then formed substantial tumors in mice(8)

(Fig. 2C).

The potency of PGRN as a tumorigenic agent was

demonstrated using primary human cells from ovarian

epithelia(20) and uterine smooth muscle.(12) Human primary

cells are difficult to transform by gene transfer in culture,(85)

requiring at minimum the increased expression of telomerase

activity, blockade of the retinoblastoma (Rb) tumor suppressor

system, and a strong mitotic drive provided in most

experiments by oncogenes such as mutant RAS. PGRN



can substitute for RAS in the transformation process. The

combination of telomerase (Tert) and SV40 T-antigen (to

block the Rb and P53 tumor suppressors) immortalized, but

did not transform primary human ovarian cells(20) or uterine

smooth muscle cells,(12) but when GRN was included with

Tert and SV40, the primary cells became very tumorigenic in

mice.(12,20) It is interesting to speculate whether this is related

to the unusual property of PGRN as a conjoint competence

and progression factor, although at present experimental

evidence neither supports nor refutes this hypothesis.

PGRN supports tumor growth by increased prolifera-

tion,(8,15) decreased apoptosis,(9,29,86–88) and greater inva-

siveness through the ECM.(9,19) Each of these actions

requires the activity of the ERK and PI3K signal transduction

pathways, although the extent to which either pathway

contributes is variable.(16) If PGRN promotes tumor growth

as we propose here, blocking its action should block tumor

growth. As discussed above, attenuating PGRN mRNA

inhibits tumor growth of cancer cells in mouse models, but

this might mean only that losing PGRN prevents the ability of

the cells to seed. Is the depletion of PGRN relevant when

dealing with large established tumors?

When liver cancer cells were transplanted into mice,

allowed to form tumors and then exposed to injections of a

PGRN monoclonal antibody, tumor growth was impeded by

approximately 50%.(25) Treating cancers in mice is far from

treating people, but the liver cancer experiments show that

PGRN has potential as a cancer drug target and is an

extremely promising area for future investigation. Interest-

ingly, the PGRN monoclonal antibodies not only inhibited

proliferation of the cancer cells directly, but also had a striking

anti-angiogenic action,(25) possibly due to decreased secre-

tion of the angiogenic growth factor VEGF in the treated

tumors,(19) although given that PGRN stimulated angiogen-

esis in wounds,(28) a more direct effect on tumor vasculariza-

tion can be postulated.

Progranulin interaction withother proteins

Extracellular protein-protein interactions regulate the activity

of many growth factors, and PGRN is no exception. During

inflammation, neutrophils release proteases such as elastase

and proteinase-3 that digest PGRN into its individual GRN

domains, which are then liberated as 6 kDa GRN peptides. In

many instances the GRN peptides oppose the effects of intact

PGRN. Thus while PGRN stimulates proliferation and inhibits

the actions of TNF-a on neutrophils,(29,30) some of the GRN

peptides inhibit cell proliferation,(36) and stimulate inflamma-

tion by eliciting the secretion of interleukin-8.(29) The critical

balance between intact PGRN and the 6 kDa GRN peptides is

maintained by a third party, the secretory leukocyte protease


inhibitor (SLPI), which binds PGRN, and prevents proteolysis

by neutrophil proteases. The activity of PGRN in a wound, or

other site of inflammation, depends therefore on the levels of

PGRN itself, the protective factor SLPI, and the neutrophil

proteases (Fig. 2D). The significance of the triad effect –

PGRN, SLPI, proteases – has been confirmed in compound

knockouts of neutrophil elastase and proteinase-3(30) and in

slpi knockout mice whose severely disrupted wound repair

could be rescued by treating the wounds with PGRN.(29)

Moreover, the SLPI-PGRN interaction is not limited to

inflammation since it has been implicated in ovarian tumor

progression.(89,90)

The interplay of proteases and PGRN may be a wide-

spread determinant of PGRN activity. Metalloproteinases

such as MMP-14(91) and ADAMTS-7(92) (a disintegrin and

metalloproteinase with thrombospondin-7) digest PGRN, with

ADAMTS-7 inactivating the growth factor-like effects of

PGRN during endochondral bone formation.(92) This interac-

tion has also been implicated in the pathogenesis of

arthritis.(93) PGRN binds the ECM proteins perlecan(94) and

chondrocyte oligomeric matrix protein (COMP);(95) the

perlecan interaction decreases the proliferative activity of

PGRN, whereas the COMP interaction enhances it. In both

cases PGRN binds its partner weakly, with affinities in the

micromolar range,(94,95) and associateswith the target protein

through an EGF-containing module. PGRN reportedly binds

the membrane protein Dlk,(96) which is also rich in EGF

modules, and although not yet tested, an affinity for EGF

modules may prove a recurrent pattern in PGRN-protein

interactions. Interactions of PGRN with intracellular proteins

such as cyclin T havebeen reported, although their physiological

significance is uncertain.(97)

GRN knockout and transgenic models

Grn knockout mice display behavioral abnormalities but few

other recorded phenotypes.(79) Given the biological actions

that have been attributed to PGRN, the mild knockout

phenotype suggests that PGRN is a molecular generalist,

contributing to many tasks but acutely essential for few.

Dissecting the biological functions of PGRN is being revealed

through conditional transgenic and knockout strategies. For

instance, keratinocyte-specific over-expression of PGRN

leads to abnormal hair development, suggesting a role for

PGRN in maintenance of hair follicles.(98)

Conclusion

When we first identified the GRN peptides as minor side

fractions on a chromatogram, there was nothing to suppose

that what would emerge was an extracellular signaling

1251


gene family that extends back to green plants and slime mold,

or that would be implicated in so many biological functions. In

recent years knowledge of the structure and function of

products ofGRN gene expression has expanded enormously,

particularly in the areas of cancer and neurobiology, but also

in the fields of development, tissue repair, and inflammation.

Much remains to be discovered, and hopefully the next few

years will see breakthroughs that will put the latest insights on

a firm footing through identification of PGRN receptors and

binding proteins, definition of its function in nerve cells, and its

application as a therapeutic target.

Acknowledgments: The research carried out in the labora-

tories of the authors and reviewed in this article was sup-

ported by grants from the Canadian Institutes for Health

Research, the National Cancer Institute of Canada, and

the Canadian Breast Cancer Research Association Ideas

Program. We gratefully acknowledge Dr. Thomas D. Bird,

University of Washington School of Medicine, Seattle, for

permission to use the image in Fig. 2A.

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The granulin gene family: from cancer to dementia

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