Reciprocal regulation of Abl kinase by Crk Y251 and Abi1 controls invasive phenotypes in glioblastoma

Abstract

Crk is the prototypical member of a class of Src homology 2 (SH2) and Src homology 3 (SH3) domain-containing adaptor proteins that positively regulate cell motility via the activation of Rac1 and, in certain tumor types such as GBM, can promote cell invasion and metastasis by mechanisms that are not well understood. Here we demonstrate that Crk, via its phosphorylation at Tyr251, promotes invasive behavior of tumor cells, is a prominent feature in GBM, and correlating with aggressive glioma grade IV staging and overall poor survival outcomes. At the molecular level, Tyr251 phosphorylation of Crk is negatively regulated by Abi1, which competes for Crk binding to Abl and attenuates Abl transactivation. Together, these results show that Crk and Abi1 have reciprocal biological effects and act as a molecular rheostat to control Abl activation and cell invasion. Finally, these data suggest that Crk Tyr251 phosphorylation regulate invasive cell phenotypes and may serve as a biomarker for aggressive GBM.

Enabling Tumor Growth and Progression: Recent Progress in Unraveling the Functions of ABL Kinases in Solid Tumor Cells

“…Binding of proteins to the ABL1/2 SH3 domains or PxxP motifs also induces loss of autoinhibition, and thus, contributes to their activation in solid tumors. Birge and colleagues demonstrate that binding of the negative regulator, Abi1, to ABL1 polyproline motifs in GBM cells, competitively inhibits binding and subsequent phosphorylation of the ABL1 substrate, CRK, which binds the same motifs [52]. Moreover, phosphorylation of CRK induces a feedforward mechanism to further activate ABL1 [52].…”

“…Birge and colleagues demonstrate that binding of the negative regulator, Abi1, to ABL1 polyproline motifs in GBM cells, competitively inhibits binding and subsequent phosphorylation of the ABL1 substrate, CRK, which binds the same motifs [52]. Moreover, phosphorylation of CRK induces a feedforward mechanism to further activate ABL1 [52]. Thus, differential binding of Abi1 and CRK controls the invasive behavior of GBM cells, and GBMs harboring low levels of Abi1 and high levels of pCrk-Y251 may serve as a biomarker for GBMs that are more likely to respond to imatinib [52].…”

“…Moreover, phosphorylation of CRK induces a feedforward mechanism to further activate ABL1 [52]. Thus, differential binding of Abi1 and CRK controls the invasive behavior of GBM cells, and GBMs harboring low levels of Abi1 and high levels of pCrk-Y251 may serve as a biomarker for GBMs that are more likely to respond to imatinib [52]. …”

“…Likewise, depletion of integrin α3β1 increases RHOA/YAP/TAZ activation and prostate cancer invasion/metastasis by inhibiting ABL1/ABL2 signaling [123]. Similarly, although ABL1 activation promotes invasion in some GBM models [52], permanent silencing of ABL1 in PC-3 cells increases invasiveness, although it also simultaneously inhibits proliferation, tumor growth, and stem cell features [67]. Thus, ABL kinases may promote or inhibit invasion depending on the signal and may act to switch cells between invasive and proliferative states.…”

Acute myeloid leukemia with t(10;11)(p11‐12;q23.3): Results of Russian Pediatric AML registration study

“…When overexpressed, ABI1 inhibits cell growth, therefore functioning as a tumor suppressor. ABI1 tumor suppressor properties were clearly demonstrated on human gastric carcinoma and glioblastoma . KMT2A‐ABI1 ‐driven leukemogenesis is hypothesized to result from the repression of normal ABI1 function by the rearranged gene product …”