Elsevier

Cellular Signalling

Volume 18, Issue 11, November 2006, Pages 1834-1843
Cellular Signalling

Review
Coupling receptor tyrosine kinases to Rho GTPases—GEFs what's the link

https://doi.org/10.1016/j.cellsig.2006.01.022Get rights and content

Abstract

Rho GTPases are molecular switches involved in the regulation of many cellular processes. This review summarizes work examining how stimulation of receptor tyrosine kinases (RTKs) leads to the activation of Rho guanine nucleotide exchange factors (GEFs) and their Rho GTPase substrates. The collective findings strongly suggest that RTK signaling to Rho proteins is a general signal transduction mechanism, like RTK mediated activation of phosphatidyl inositol 3-kinase, phospholipase Cγ, and the mitogen activated protein kinase (MAPK) pathway. More than half of the 58 known human RTKs activate at least one Rho family member. Likewise, 16 Rho GEFs directly interact with and/or are phosphorylated by a RTK. The specificity of receptor tyrosine kinase/Rho GEF signaling seems to be somewhat promiscuous. There several cases where multiple RTKs activate the same Rho GEF and where a single RTK can activate multiple Rho GEFs. Expression analysis indicates that the average human tissue contains transcripts for 33 RTKs, 34 Rho GEFs, and 14 Rho GTPases with each tissue containing a unique complement of these proteins. Given the promiscuity of RTKs for Rho GEFs, Rho GEFs for Rho GTPases, and the large number of these proteins expressed in cells, a complex combinatorial network of proteins in these families may contribute to coding specific signals and cell responses from RTKs.

Introduction

Many of the pathways that transduce signals from cell surface receptors to the nucleus involve at least one G-protein. G-proteins act as molecular switches being inactive when bound to GDP and bind a variety of effector proteins when bound to GTP in their active conformation. G-proteins are controlled by guanine nucleotide exchange factors (GEFs) which destabilize the inactive GDP/G-protein complex inducing release of GDP, and binding of cytosolic GTP, activating the G-protein. GTPase activating proteins (GAPs) induce the hydrolysis of GTP bound to G-proteins deactivating the G-protein switch and guanine nucleotide dissociation inhibitors can sequester G-proteins bound to either GTP or GDP.

Many receptors are known to activate G-proteins. The majority of receptors in mammalian proteomes are serpentine G-protein coupled receptors (GPCRs) and the principal signaling mechanism for receptors in this family involves direct activation of heterotrimeric G-proteins and their downstream signaling pathways. Another superfamily of G-proteins (Ras) encompasses the Ras, Rab, Arf, Ran, and Rho families [1]. In general, Rabs and Arfs are involved in protein trafficking, Ras is involved in signal transduction, Ran is involved in nuclear export and Rho proteins are involved in modulation of the actin cytoskeleton. Rho proteins in their active GTP-bound form, bind to a rapidly expanding group of effector proteins that effect many cell processes [2]. Through binding these effectors, Rho family members play important roles as controllers of actin cytoskeleton, and related cell motility and chemotactic responses. In addition, Rho GTPases and the Rho GEFs that activate these Rho proteins play additional roles in cell adhesion, cytokinesis, cell-cycle progression, macropinocytosis, endocytosis, membrane trafficking, and signal transduction [3].

The Rho family GTPases are activated by Rho GEFs. Because Rho proteins affect so many different cellular processes, they are attractive candidates for processing incoming receptor signals similar to the activation of heterotrimeric G proteins by GPCRs. The general role of Rho GTPases in signal transduction was last reviewed in 2000 [4]. At the time of this review, several GPCRs were known to activate a Rho GTPase and p115, PDZ, or Lbc Rho GEFs were activated by Gα subunits of heterotrimeric G-proteins. The activation of Rho GTPases by GPCRs, was recently reviewed [5]. These reviews do not cover the now emerging connection between the receptor tyrosine kinase and Rho GTPase families. Over the past 5 years the coupling between receptor tyrosine kinases and activation of Rho GTPases has become evident. Activation of Rho GTPases, is probably a general property of receptor tyrosine kinase signaling and is the subject of this review.

Section snippets

Receptor tyrosine kinases that activate Rho proteins

About 35 years ago, through studies applying insulin, epidermal growth factor, and nerve growth factor to cells, the first cell-surface receptors were identified [6], [7], [8], [9], [10]. In the early 1980s, the Insulin receptor was shown to possess tyrosine autokinase activity and this family has become known as the receptor tyrosine kinase (RTK) family [11], [12]. The human genome encodes 58 RTKs as recognized to date [13] (Fig. 1). Several years later the connection between growth factor

Rho GEFs that link RTKs to Rho GTPase activation

Since so many RTK are known to activate Rho GTPases, there is a strong link between these protein families. Therefore, one would expect Rho GEFs, as activators of GTPases also to be connected with RTKs. At least 16 of the 69 known Rho GEFs (from humans) have been shown to mediate the connection between RTKs and Rho GTPase activation, as summarized in Table 1.

Several Rho GEFs seem to be somewhat promiscuous, mediating signals from several different RTKs. Vav2 activates Rac1 through stimulation

RTKs signal through Rho GEFs by multiple mechanisms

Unlike the connection of RTKs to Ras activation, there seems to be no unifying mechanism by which RTKs can activate Rho GTPases. In one type of mechanism, RTKs can activate Rho GTPases indirectly as downstream signaling events. Stimulation of PDGFRB and EPHB2 induces receptor autophosphorylation and docking of the SH2 domain of the p85 subunit of PI3K. PI3K recruits α-Pix which mediates the activation of Cdc42 and Rac1 [43]. Binding of a Nck/Pak complex to the RTK may also be involved in

RTKs phosphorylate Rho GEFs on tyrosine residues, inducing their GEF activity

The mechanisms by which Rho GEFs are regulated have been previously reviewed [47], [48]. Perhaps the best understood mechanism of Rho GEF activation is that of Vavs where tyrosine phosphorylation of the Tyr172 residue N-terminal to the Dbl-homology domain relieves autoinhibition by allowing access to Rho substrates [49], [50], [51].

Several pieces of evidence suggest that RTK mediated tyrosine phosphorylation of Rho GEFs is a widely used mechanism for activation of many Rho GEFs. As detailed

Pleckstrin homology domains that mediate RTK–Rho GEF interactions

Pleckstrin homology domains are best known for their interaction with phosphoinositide lipids and are present in many proteins including nearly all Rho GEFs. In addition to tyrosine phosphorylation, several studies suggest that the PH domains of Rho GEFs may play a major role in coupling several RTKs to Rho GEFs. The PH domain of Vav2 is required for EGF stimulated activation of Vav2 and Rac1. This is thought to be mediated through PI3K production of PIP3 and PIP3 binding to the PH domain of

Other Rho GEF domains that bind RTKs

The previous sections summarize the importance of binding of RTKs to SH2 and PH domains in several Rho GEFs. Several other domains in Rho GEFs are involved in binding RTKs. EPHA2 binds directly to Tiam through its N-terminal region and Ephrin induced activation of Rac1 depends on Tiam (Fig. 2) [46]. Also, the PDZ domain of the Rho GEF Larg interacts with the C-terminal domain of the IGF1R and mediates IGF signaling to RhoA [25]. P-Rex1 Rho GEF is involved in TRKA mediated activation of Rac.

Domains of RTKs that bind Rho GEFs

In addition to knowing which domains of RhoGEFs bind to RTKs, to understand the relationship between Rho GEFs and RTKs it is also important to know which domains of the RTK interact with the Rho GEF (Fig. 2). RTKs have juxtamembrane regions, tyrosine kinase domains, and a C-terminal tail. Like the different domains of Rho GEFs that bind RTKs, all three regions of RTKs are known to interact with RhoGEFs. Both RasGrf1 and Kalirin interact with the juxtamembrane regions of TRKA [54] (Schiller,

Cells may contain many RTK, Rho GEF and RhoGTPase family members

Since the RTK, Rho GEF, and RhoGTPase families have many family members that are not well characterized, we wanted to better understand the potential relationship between these families. To do so, expression profiles for human transcripts in 31 different tissues were compared using the Gene expression profile viewer in the Unigene database (see supplemental data) [72]. Expression of Rho proteins in the 31 tissues varied, ranging from 8 Rho transcripts present in the small intestine to all 20 in

Are Rho GEFs and GTPases involved in RTK signal transduction specificity?

All RTKs are thought to signal through the MAPK, PI3K and PLCγ1 pathways, yet generate different cellular responses. Perhaps the best example of these differential responses is that of PC12 cells, which contain at least 15 receptor tyrosine kinases that can induce neurite outgrowth, glucose uptake, mitogenesis, or cell survival (Fig. 5).

Three main hypotheses have emerged to explain how cells achieve specific responses from different RTKs. One hypothesis suggests that differing kinetics of Erk

Acknowledgments

I would like to thank Drs. Bruce Mayer and Richard Mains for their assistance in preparation of this manuscript. I would also like to acknowledge Winfred Krueger for his help in the cluster analysis of the data for the expression analysis.

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