Figure 2. Proposed mechanism of Abl regulation of CAS/Crk coupling and membrane protrusion.

Figure 2

Proposed mechanism of Abl regulation of CAS/Crk coupling and membrane protrusion. Step 1) Growth factor and integrin receptor activation facilitates the assembly of a CAS/Crk/DOCK180/Rac signaling scaffold that promotes actin-mediated lamellipodium protrusion.20,21 Step 2) Abl is also activated under these conditions and serves as a negative-feedback signal that modulates the level of CAS/ Crk coupling in cells through phosphorylation of tyrosine 221 (Y221) in Crk.22 Step 3) Phosphorylated Crk then undergoes intramolecular folding in which its own SH2 domain binds to phosphorylated Y221. This in turn exposes a proline rich region (PXXP) within the Crk-SH2 domain, which can interact with the SH3 domain of Abl forming a stable complex.29 Step 4) The Abl/Crk complex is then translocated to the membrane and/or focal adhesions where it is dephosphorylated by protein tyrosine phosphatase-1B (PIP-1B).21 Step 5) This facilitates the disassembly of Abl and Crk, enabling Crk to unfold and interact with the CAS protein scaffold. The cycle is then repeated as new protrusions and focal adhesions form in the leading lamellipodium during cell migration. Src homology 2 (SH2), Src homology 3 (SH3), polyproline sequence (PPP), kinase domain (KD).

From: Regulation of Cell Motility by Abl Family Kinases

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