In response to integrin receptor binding to the extracellular matrix, the multidomain docking protein p130(cas) (Crk-associated substrate) activates various signaling cascades modulating such cellular processes as proliferation, migration, and apoptosis. During apoptosis, caspase-mediated cleavage of p130(cas) generated a C-terminal 31-kDa fragment (31-kDa) and promoted morphological changes characteristic of apoptosis, including loss of focal adhesions, cell rounding, and nuclear condensation and fragmentation. By contrast, a p130(cas) D748E mutant, which was unable to produce 31-kDa, attenuated the disassembly of focal adhesions at the bottom of the cell. 31-kDa contains a helix-loop-helix (HLH) domain that shows greater sequence homology with Id proteins than with basic HLH proteins, which enabled heterodimerization with E2A. Once coupled to E2A, 31-kDa was translocated to the cell nucleus, where it inhibited E2A-mediated p21(Waf1/Cip1) transcription. Moreover, overexpression of 31-kDa led to cell death that could be inhibited by treatment with the caspase inhibitor ZVAD-fluoromethyl ketone or by ectopic expression of E2A or p21(Waf1/Cip1). These data suggest that during etoposide-induced apoptosis, 31-kDa promotes caspase-mediated cell death by inhibiting E2A-mediated activation of p21(Waf1/Cip1) transcription.
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