Dock-family exchange factors in cell migration and disease

doi:10.1016/j.ejcb.2014.06.003

European Journal of Cell Biology

Volume 93, Issues 10–12, October 2014, Pages 466-477

https://doi.org/10.1016/j.ejcb.2014.06.003 Get rights and content

Abstract

Dock family proteins are evolutionary conserved exchange factors for the Rho GTPases Rac and Cdc42. There are 11 Dock proteins in mammals, named Dock1 (or Dock180) to Dock11 that play different cellular functions. In particular, Dock proteins regulate actin cytoskeleton, cell adhesion and migration. Not surprisingly, members of the Dock family have been involved in various pathologies, including cancer and defects in the central nervous and immune systems. This review proposes an update of the recent findings regarding the function of Dock proteins, focusing on their role in the control of cell migration and invasion and the consequences in human diseases.

Introduction

Cell adhesion and migration are regulated by a wide variety of chemical and physical extracellular cues: cytokines, growth factors, tension, shear stress, stiffness… These signals are transmitted to the intracellular medium by membrane receptors such as cytokine and growth factor receptors, integrin and cadherin adhesion receptors. Such receptors further drive the reorganization of the actin cytoskeleton downstream of the activation of Rho GTPases by their exchange factors.

There are 20 Rho GTPases in the human genome, among which RhoA, Rac1 and Cdc42 are the most studied (Boureux et al., 2007). Two classes of exchange factors were described for Rho GTPases: the classical Dbl-related exchange factors and more recently the atypical Dock family exchange factors. Dbl/MCF2 was described as an activator of Rho GTPases in 1984. Since then, about 80 Dbl-related proteins were identified. They are characterized by a 200 amino acid Dbl-homology (DH) domain, which catalyzes the nucleotide exchange reaction. They have been widely studies for their functions in regulating cell adhesion and migration via the activation of Rho GTPases. Several among the 80 Dbl-related GEFs have been involved in different types of cancers and various pathologies including central nervous system and immune system (Cook et al., 2013). The Dock-family of exchange factors emerged only 12 years ago as a novel class of Rho GTPase activators, in particular of Rac(1/2/3) and Cdc42 (Cote and Vuori, 2002). Since then, they have been involved in the regulation of a wide variety of cellular pathways downstream of membrane receptors (Fig. 1). Here we propose an overview of the signaling pathways involving the GEFs of the Dock family, their impact on cell adhesion and migration and their implication in cancer and various pathologies (Table 1).

Section snippets

Dock protein-mediated activation of Rho GTPases

The human genome contains 11 genes encoding Dock1-related proteins that function as exchange factors (GEFs) for the Rho GTPases Rac and Cdc42. Dock proteins are qualified atypical Rho GTPase GEFs (Rho GEFs) as compared to the typical Dbl family of Rho GEFs. Dock proteins are large polypeptides characterized by the presence of two domains: DHR1 (or Docker or CZH1) domain, which is 200–250 aminoacid long and binds phospholipids, and DHR2 (or CZH2) domain that is 450–550 aminoacid long and bears

Dock1 in cell migration and cancer

Dock1 or Dock180 is the prototypic member of the Dock protein family that was identified originally as a partner for Crk (Hasegawa et al., 1996) and was further shown to activate Rac (Kiyokawa et al., 1998a). The amino-terminal SH3 domain of Dock1 functions as an intramolecular inhibitor of the exchange factor, which can be relieved upon its binding to the ELMO 1–3 adaptor proteins, after their binding to active RhoG at the plasma membrane (Katoh and Negishi, 2003, Lu et al., 2004, Lu et al.,

Dock3

Dock3 also known as PBP (Presenilin Binding Partner) or MOCA (Modifier Of Cell Adhesion protein) is specifically expressed in neurons and was first identified as an interactor of Presenilin (Kashiwa et al., 2000). Presenilin, which mutation was found responsible for Alzheimer's neurodegenerative disorder, are implicated in the regulation of intracellular calcium and neuronal cell death (Keller et al., 1998). As a binding partner of Presenilin, Dock3 is now considered as a major integrator of

Conclusions

Over the last 10 years, Dock proteins emerged as major regulators of actin dynamics to mediate cell adhesion and migration responses downstream of growth factor, cytokine and adhesion receptors. Consequently, an increasing number of reports point at their involvement in various pathological processes including cancer. Although a lot remains to be uncovered, many regulatory mechanisms have already been shown to control the activation of the enzymatic exchange activity of Dock proteins on Rac and

Acknowledgements

This work was funded by grants from the Institut National du Cancer (Grant # INCa-4361 to AB), the Agence Nationale de la Recherche (Grant # ANR-2011-BLAN-006 to AB).

References (134)

A. Barrett et al.
p130Cas: a key signalling node in health and disease
Cell. Signal.
(2013)
G. Chen et al.
Inhibition of chemokine (CXC motif) ligand 12/chemokine (CXC motif) receptor 4 axis (CXCL12/CXCR4)-mediated cell migration by targeting mammalian target of rapamycin (mTOR) pathway in human gastric carcinoma cells
J. Biol. Chem.
(2012)
J.F. Cote et al.
In vitro guanine nucleotide exchange activity of DHR-2/DOCKER/CZH2 domains
Methods Enzymol.
(2006)
J.F. Cote et al.
GEF what? Dock180 and related proteins help Rac to polarize cells in new ways
Trends Cell Biol.
(2007)
G. Crawford et al.
DOCK8 is critical for the survival and function of NKT cells
Blood
(2013)
P. Duchek et al.
Guidance of cell migration by the Drosophila PDGF/VEGF receptor
Cell
(2001)
R. Fritsch et al.
RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms
Cell
(2013)
G. Gadea et al.
DOCK10-mediated Cdc42 activation is necessary for amoeboid invasion of melanoma cells
Curr. Biol.
(2008)
K. Gotoh et al.
Differential requirement for DOCK2 in migration of plasmacytoid dendritic cells versus myeloid dendritic cells
Blood
(2008)
C.M. Grimsley et al.
Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration
J. Biol. Chem.
(2004)

W. Guo et al.

Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis

Cell

(2006)

Y. Harada et al.

DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses

Blood

(2012)

K. Hiramoto et al.

Dock4 is regulated by RhoG and promotes Rac-dependent cell migration

Exp. Cell Res.

(2006)

R. Hosokawa et al.

Functional significance of Smad2 in regulating basal keratinocyte migration during wound healing

J. Invest. Dermatol.

(2005)

J.O. Humtsoe et al.

Transcriptional profiling identifies upregulated genes following induction of epithelial–mesenchymal transition in squamous carcinoma cells

Exp. Cell Res.

(2012)

M. Kim et al.

Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene

Cell

(2006)

E. Kiyokawa et al.

Evidence that DOCK180 up-regulates signals from the CrkII–p130(Cas) complex

J. Biol. Chem.

(1998)

M. Kobayashi et al.

Dock4 forms a complex with SH3YL1 and regulates cancer cell migration

Cell. Signal.

(2014)

K. Kulkarni et al.

Multiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nucleotide exchange factors

J. Biol. Chem.

(2011)

Q. Lin et al.

Identification of a DOCK180-related guanine nucleotide exchange factor that is capable of mediating a positive feedback activation of Cdc42

J. Biol. Chem.

(2006)

M. Lu et al.

A steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs

Curr. Biol.

(2005)

Y. Margaron et al.

ELMO recruits actin cross-linking family 7 (ACF7) at the cell membrane for microtubule capture and stabilization of cellular protrusions

J. Biol. Chem.

(2013)

Y. Miyamoto et al.

Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth

Exp. Cell Res.

(2007)

A. Nishikimi et al.

Immune regulatory functions of DOCK family proteins in health and disease

Exp. Cell Res.

(2013)

A. Nishikimi et al.

Zizimin2: a novel, DOCK180-related Cdc42 guanine nucleotide exchange factor expressed predominantly in lymphocytes

FEBS Lett.

(2005)

C. Nombela-Arrieta et al.

Differential requirements for DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing

Immunity

(2004)

N. Omi et al.

Mutation of Dock5, a member of the guanine exchange factor Dock180 superfamily, in the rupture of lens cataract mouse

Exp. Eye Res.

(2008)

A.T. Pagnamenta et al.

Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia

Biol. Psychiatry

(2010)

M. Patel et al.

An evolutionarily conserved autoinhibitory molecular switch in ELMO proteins regulates Rac signaling

Curr. Biol.

(2010)

A. Alkelai et al.

DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population

Int. J. Neuropsychopharmacol.

(2012)

K. Almstrup et al.

Improved gene expression signature of testicular carcinoma in situ

Int. J. Androl.

(2007)

Z. Alsum et al.

Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty-five patients

J. Clin. Immunol.

(2013)

R. Bhattacharyya et al.

A novel role of Rac1 GTPase in JCV T-antigen-mediated beta-catenin stabilization

Oncogene

(2007)

A.L. Blasius et al.

Mice with mutations of Dock7 have generalized hypopigmentation and white-spotting but show normal neurological function

Proc. Natl. Acad. Sci. U.S.A.

(2009)

A. Boureux et al.

Evolution of the Rho family of ras-like GTPases in eukaryotes

Mol. Biol. Evol.

(2007)

H. Brazier et al.

Expression profile of RhoGTPases and RhoGEFs during RANKL-stimulated osteoclastogenesis: identification of essential genes in osteoclasts

J. Bone Miner. Res.

(2006)

K.A. Brown et al.

Identification of novel Smad2 and Smad3 associated proteins in response to TGF-beta1

J. Cell. Biochem.

(2008)

E. Brugnera et al.

Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex

Nat. Cell Biol.

(2002)

F. Calvo et al.

RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation

Nat. Cell Biol.

(2011)

Q. Chen et al.

Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration

J. Neurosci.

(2009)

D.R. Cook et al.

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

Oncogene

(2013)

J.F. Cote et al.

A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signalling

Nat. Cell Biol.

(2005)

J.F. Cote et al.

Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity

J. Cell Sci.

(2002)

M. Czugala et al.

Novel mutation and three other sequence variants segregating with phenotype at keratoconus 13q32 susceptibility locus

Eur. J. Hum. Genet.

(2012)

S.D. Detera-Wadleigh et al.

Sequence variation in DOCK9 and heterogeneity in bipolar disorder

Psychiatr. Genet.

(2007)

S. Edlund et al.

Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA

Mol. Biol. Cell

(2002)

S. Edlund et al.

Smad7 is required for TGF-beta-induced activation of the small GTPase Cdc42

J. Cell Sci.

(2004)

R. Faccio et al.

Vav3 regulates osteoclast function and bone mass

Nat. Med.

(2005)

H. Feng et al.

Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis

Proc. Natl. Acad. Sci. U.S.A.

(2012)

H. Feng et al.

Activation of Rac1 by Src-dependent phosphorylation of Dock180(Y1811) mediates PDGFRalpha-stimulated glioma tumorigenesis in mice and humans

J. Clin. Invest.

(2011)

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Mini ReviewDock-family exchange factors in cell migration and disease

Abstract

Introduction

Section snippets

Dock protein-mediated activation of Rho GTPases

Dock1 in cell migration and cancer

Dock3

Conclusions

Acknowledgements

Cell. Signal.

J. Biol. Chem.

Methods Enzymol.

Trends Cell Biol.

Blood

Cell

Cell

Curr. Biol.

Blood

J. Biol. Chem.

Cell

Blood

Exp. Cell Res.

J. Invest. Dermatol.

Exp. Cell Res.

Cell

J. Biol. Chem.

Cell. Signal.

J. Biol. Chem.

J. Biol. Chem.

Curr. Biol.

J. Biol. Chem.

Exp. Cell Res.

Exp. Cell Res.

FEBS Lett.

Immunity

Exp. Eye Res.

Biol. Psychiatry

Curr. Biol.

DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population

Int. J. Neuropsychopharmacol.

Improved gene expression signature of testicular carcinoma in situ

Int. J. Androl.

Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty-five patients

J. Clin. Immunol.

A novel role of Rac1 GTPase in JCV T-antigen-mediated beta-catenin stabilization

Oncogene

Mice with mutations of Dock7 have generalized hypopigmentation and white-spotting but show normal neurological function

Proc. Natl. Acad. Sci. U.S.A.

Evolution of the Rho family of ras-like GTPases in eukaryotes

Mol. Biol. Evol.

Expression profile of RhoGTPases and RhoGEFs during RANKL-stimulated osteoclastogenesis: identification of essential genes in osteoclasts

J. Bone Miner. Res.

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J. Cell. Biochem.

Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex

Nat. Cell Biol.

RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation

Nat. Cell Biol.

Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration

J. Neurosci.

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

Oncogene

A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signalling

Nat. Cell Biol.

Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity

J. Cell Sci.

Novel mutation and three other sequence variants segregating with phenotype at keratoconus 13q32 susceptibility locus

Eur. J. Hum. Genet.

Sequence variation in DOCK9 and heterogeneity in bipolar disorder

Psychiatr. Genet.

Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA

Mol. Biol. Cell

Smad7 is required for TGF-beta-induced activation of the small GTPase Cdc42

J. Cell Sci.

Vav3 regulates osteoclast function and bone mass

Nat. Med.

Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis

Proc. Natl. Acad. Sci. U.S.A.

Activation of Rac1 by Src-dependent phosphorylation of Dock180(Y1811) mediates PDGFRalpha-stimulated glioma tumorigenesis in mice and humans

J. Clin. Invest.

Mini Review
Dock-family exchange factors in cell migration and disease