FAK-mediated src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation.
Focal adhesion kinase (FAK) is an important mediator of integrin signaling in the regulation of cell proliferation, survival, migration, and invasion. To understand how FAK contributes to cell invasion, we explored the regulation of matrix metalloproteinases (MMPs) by FAK. We found that v-Src-transformed cells activate a FAK-dependent mechanism that attenuates endocytosis of MT1-MMP. This in turn increases cell-surface expression of MT1-MMP and cellular degradation of extracellular matrix. Further, we identified an interaction between FAK's second Pro-rich motif and endophilin A2's SH3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow Src phosphorylation of endophilin A2 at Tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of Tyr315 phosphorylation promoted endocytosis of MT1-MMP. Together, these results suggest a regulatory mechanism of cell invasion whereby FAK promotes cell-surface presentation of MT1-MMP by inhibiting endophilin A2-dependent endocytosis.
Wu
Xiaoyang
X
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
Gan
Boyi
B
Yoo
Youngdong
Y
Guan
Jun-Lin
JL
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016391:Genes, src; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; C105159:SH3GL1 protein, human; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D034281:Dynamins