The tumor suppressor DAPK is reciprocally regulated by tyrosine kinase Src and phosphatase LAR.
Death-associated protein kinase (DAPK) is a calmodulin-regulated serine/threonine kinase and elicits tumor suppression function through inhibiting cell adhesion/migration and promoting apoptosis. Despite these biological functions, the signaling mechanisms through which DAPK is regulated remain largely elusive. Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation. Upon EGF stimulation, a rapid Src activation leads to subsequent LAR downregulation, and these two events act in synergism to inactivate DAPK, thereby facilitating tumor cell migration and invasion toward EGF. Finally, DAPK Y491/492 hyperphosphorylation is found in human cancers in which Src activity is aberrantly elevated. These results identify LAR and Src as a DAPK regulator through their reciprocal modification of DAPK Y491/492 residues and establish a functional link of this DAPK-regulatory circuit to tumor progression.
Wang
Won-Jing
WJ
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Kuo
Jean-Cheng
JC
Ku
Wei
W
Lee
Yu-Ru
YR
Lin
Feng-Chi
FC
Chang
Yih-Leong
YL
Lin
Yu-Min
YM
Chen
Chun-Hau
CH
Huang
Yuan-Ping
YP
Chiang
Meng-Jung
MJ
Yeh
Sheng-Wen
SW
Wu
Pei-Rung
PR
Shen
Che-Hung
CH
Wu
Chen-Tu
CT
Chen
Ruey-Hwa
RH
D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism / Q000502:physiology*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*