SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration.
EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF-induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here, we identify SRC-3Delta4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src. We identify three PAK1-mediated phosphorylations in SRC-3Delta4 that promote the localization of SRC-3Delta4 to the plasma membrane and mediate the interactions with EGFR and FAK. Importantly, overexpression of SRC-3Delta4 promotes MDA-MB231-induced breast tumor metastasis. Our findings identify phosphorylated SRC-3Delta4 as a missing adaptor between EGFR and its downstream signaling molecule FAK to coordinately regulate EGF-induced cell migration. Our study also reveals that a nuclear receptor coactivator can act in the periphery of a cell to directly mediate activation of an enzyme.
Long
Weiwen
W
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030 USA.
Yi
Ping
P
Amazit
Larbi
L
LaMarca
Heather L
HL
Ashcroft
Felicity
F
Kumar
Rakesh
R
Mancini
Michael A
MA
Tsai
Sophia Y
SY
Tsai
Ming-Jer
MJ
O'Malley
Bert W
BW
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D051379:Mice; D009362:Neoplasm Metastasis; D056921:Nuclear Receptor Coactivator 3 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology
D020033:Protein Isoforms; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C512478:EGFR protein, human; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D054462:p21-Activated Kinases