Pseudopodium-enriched atypical kinase 1 regulates the cytoskeleton and cancer progression [corrected].
Regulation of the actin-myosin cytoskeleton plays a central role in cell migration and cancer progression. Here, we report the discovery of a cytoskeleton-associated kinase, pseudopodium-enriched atypical kinase 1 (PEAK1). PEAK1 is a 190-kDa nonreceptor tyrosine kinase that localizes to actin filaments and focal adhesions. PEAK1 undergoes Src-induced tyrosine phosphorylation, regulates the p130Cas-Crk-paxillin and Erk signaling pathways, and operates downstream of integrin and epidermal growth factor receptors (EGFR) to control cell spreading, migration, and proliferation. Perturbation of PEAK1 levels in cancer cells alters anchorage-independent growth and tumor progression in mice. Notably, primary and metastatic samples from colon cancer patients display amplified PEAK1 levels in 81% of the cases. Our findings indicate that PEAK1 is an important cytoskeletal regulatory kinase and possible target for anticancer therapy.
Wang
Yingchun
Y
Department of Pathology, Moores Cancer Center, University of California, La Jolla, CA 92093, USA.
Kelber
Jonathan A
JA
Tran Cao
Hop S
HS
Cantin
Greg T
GT
Lin
Rui
R
Wang
Wei
W
Kaushal
Sharmeela
S
Bristow
Jeanne M
JM
Edgington
Thomas S
TS
Hoffman
Robert M
RM
Bouvet
Michael
M
Yates
John R
JR
Klemke
Richard L
RL
D000199:Actins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism; D019295:Computational Biology; D003599:Cytoskeleton / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000209:etiology / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D011554:Pseudopodia / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
D000199:Actins; D017931:DNA Primers; D011993:Recombinant Fusion Proteins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases