Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: a perspective

Abstract

Cell migration is critical for many physiological processes and is often misregulated in developmental disorders and pathological conditions including cancer and neurodegeneration. MAPK signaling and the Rho family of proteins are known regulators of cell migration that exert their influence on cellular cytoskeleton during cell adhesion and migration. Here we review data supporting the view that localized ERK signaling mediated through recently identified scaffold proteins may regulate cell migration.

Fig. 1

Rho family of proteins regulate actin and microtubule dynamics. A) Membrane protrusion is governed by regulated assembly and disassembly of actin cytoskeleton. Activated Rac and Cdc42 respectively activate WAVE and WASP family of proteins to regulate actin polymerization through Arp2/3. Steady state actin bundles are maintained by the opposing effects of profilin-dependent assembly and cofilin-dependent disassembly. B) The Rho effector, mDia is required for stabilization of microtubules. Stable microtubules perhaps transport activated Rac to membrane protrusions. PAK, the downstream effector of Rac/Cdc42, and ERK downstream of activated PAK promote microtubule polymerization by inhibiting stathmin’s tubulin sequestration activity thereby providing free tubulin for tubulin cofactor (TcoB) dependent α- and β- tubulin heterodimerization. PAK can directly activate TcoB and promote its tubulin polymerization activity. Microtubule dynamics may also facilitate transfer of calpain proteases in kinesin-dependent fashion to downregulate integrin signaling by proteolytic cleavage of FAK and dynamin-dependent disassembly of focal adhesions.

Fig. 2

MP1/p14 may integrate Rho and PAK signaling on endosomes. MP1/p14 regulate integrin activation of MAPK and focal adhesion disassembly. MP1/p14 bind active forms of PAK and regulate PAK phosphorylation of MEK during acute adhesion. PAK also binds and activates the dynein light chain (DLC1). We speculate that the LC7 dynein light chain motif of p14 may tether PAK-MEK-ERK-MP1 complex to dynein motors facilitating their transfer through endocytic system (A). Alternatively, MEK-ERK-MP1 complex could be activated by PAK at late endosome by virtue of p14 interaction with MP1 (B). Further transfer of this activated complex to kinesin motors could potentially traffic the complex through recycling endosomes or anterograde traffic to focal sites.

Fig. 3

An interactome of MP1/p14. Figure is a composite of in vitro and yeast two-hybrid data from mammalian cells and Drosophila. Data from whole genome interaction map from Drosophila (red arrows) (www.biogrid.com) was culled to show potential connection of MP1/p14 and ERK signaling to intracellular trafficking machinery that might be important for integrin signaling and cell migration. Novel uncharacterized interactions of MP1 suggest that it might also regulate suppressor of fused (Sufu) implicated in hedgehog (Hhg) and Wnt signaling through its interactions with Sufu-binding partners PIAS (protein inhibitor of STAT), and p300 (transcriptional coactivator). MP1 interacts with a RNA-helicase-like protein Rm62 which is a major interacting hub with 25 associations in the Drosophila interactome. Rm62 interacts either directly or indirectly to the actin cytoskeleton, dynein motors, and components of exocyst complex that regulates polarity in yeast and animals. Further, Rm62 interactions with SNAPs and SNARES might incorporate MP1 to membrane trafficking steps. Interaction of MP1 with WD-containing MORG might regulate LPA induced ERK activation whereas KSR-MP1 interaction might be required for sustaining growth factor signaling.

Fig. 4

Multiple ERK scaffold regulate growth factor and adhesion signaling. A). GPCR mediated MAPK activation is regulated by arrestin and MORG. KSR is constitutively localized to the cytoplasm and to a tubulo-vesicular recycling compartment. Pathway activation promotes membrane recruitment of KSR-MEK-ERK where the module is activated by membrane bound Raf. MP1/p14 is required for the late phase of growth factor signaling on late endosomes. B). IQGAP, an actin binding protein retains Cdc42 and Rac in their GTP bound states. MEK and ERK bound to IQGAP may be targeted to growing tips of microtubules through IQGAP interaction with CLIP170 (a +TIP). C). GRK interacting GITs regulate signaling from GPCRs and integrins. GITs possess GAP activity towards membrane traffic regulators, ARFs. The multimeric interaction of GITs couple MEK and ERK to membrane trafficking steps through the GAP functions of GIT. EV, endocytic vesicles, EE, RE and LE refer to early, recycling and late endosomes, respectively.