Oncogenic Src requires a wild-type counterpart to regulate invadopodia maturation.
The proto-oncogene Src tyrosine kinase (Src) is overexpressed in human cancers and is currently a target of anti-invasive therapies. Activation of Src is an essential catalyst of invadopodia production. Invadopodia are cellular structures that mediate extracellular matrix (ECM) proteolysis, allowing invasive cell types to breach confining tissue barriers. Invadopodia assembly and maturation is a multistep process, first requiring the targeting of actin-associated proteins to form pre-invadopodia, which subsequently mature by recruitment and activation of matrix metalloproteases (MMPs) that facilitate ECM degradation. We demonstrate that active, oncogenic Src alleles require the presence of a wild-type counterpart to induce ECM degradation at invadopodia sites. In addition, we identify the phosphorylation of the invadopodia regulatory protein cortactin as an important mediator of invadopodia maturation downstream of wild-type Src. Distinct phosphotyrosine-based protein-binding profiles in cells forming pre-invadopodia and mature invadopodia were identified by SH2-domain array analysis. These results indicate that although elevated Src kinase activity is required to target actin-associated proteins to pre-invadopodia, regulated Src activity is required for invadopodia maturation and matrix degradation activity. Our findings describe a previously unappreciated role for proto-oncogenic Src in enabling the invasive activity of constitutively active Src alleles.
Kelley
Laura C
LC
Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506-9300, USA.
Ammer
Amanda Gatesman
AG
Hayes
Karen E
KE
Martin
Karen H
KH
Machida
Kazuya
K
Jia
Lin
L
Mayer
Bruce J
BJ
Weed
Scott A
SA
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D051356:Cortactin / Q000378:metabolism*; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011554:Pseudopodia / Q000378:metabolism*; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*
D051356:Cortactin; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019061:src-Family Kinases