Neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of Src in mammary tumor cells

被引:26
|
作者
Berman-Golan, D. [1 ]
Elson, A. [1 ]
机构
[1] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel
关键词
tyrosine phosphatase; breast cancer; mammary tumor; Src; Neu;
D O I
10.1038/sj.onc.1210505
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The receptor-type protein tyrosine phosphatase epsilon (RPTPe) activates c-Src in mammary tumor cells induced in vivo by Neu. Tumor cells lacking RPTPe exhibit reduced c-Src activity, appear less transformed morphologically and proliferate slower in vitro and in vivo. Expression of Src rescues most of these phenotypes, indicating that c-Src activity is important for maintaining the transformed phenotype. However, the molecular mechanisms that control activation of c-Src by RPTPe are unknown. We show that Neu induces phosphorylation of RPTPe exclusively at its C-terminal Y695, and that this phosphorylation is required for activation of c-Src by RPTPe. Phosphorylation of RPTPe does not affect its activity toward another substrate, the voltage-gated potassium channel Kv2.1, suggesting that phosphorylation directs RPTPe activity toward c-Src. Phosphorylation of RPTPe reduces its dimerization at the cell membrane, although this does not affect its activity significantly. RPTPe is subject to strong auto-and trans-dephosphorylation, suggesting that dephosphorylation limits the activation of c-Src downstream of Neu. We conclude that an Neu-RPTP epsilon-Src signaling pathway exists in mammary tumor cells, in which phosphorylation of RPTPe by Neu directs RPTPe to activate c-Src. Reversible phosphorylation of RPTPe at Y695 may thus function as a 'molecular switch', which affects the substrate specificity of the phosphatase.
引用
收藏
页码:7028 / 7037
页数:10
相关论文
共 50 条
  • [41] Activation of protein phosphorylation by oxidants in vascular endothelial cells: Identification of tyrosine phosphorylation of caveolin
    Vepa, S
    Scribner, WM
    Natarajan, V
    FREE RADICAL BIOLOGY AND MEDICINE, 1997, 22 (1-2) : 25 - 35
  • [42] ACTIVATION OF SERINE THREONINE KINASES BY TYROSINE PHOSPHORYLATION IN CELLS TRANSFORMED BY THE V-SRC ONCOGENE
    HANAFUSA, H
    STERNBERG, D
    SCHOLZ, G
    JOURNAL OF CELLULAR BIOCHEMISTRY, 1993, : 220 - 220
  • [43] Positive regulation of osteoclast-mediated bone resorption and podosome organization by protein tyrosine phosphatase epsilon
    Granot-Attas, S.
    Luxenburg, C.
    Elson, A.
    FEBS JOURNAL, 2008, 275 : 449 - 449
  • [44] Multiple phosphorylation of chicken protein tyrosine phosphatase 1 and human protein tyrosine phosphatase 1B by casein kinase II and p60c-src in vitro
    Jung, EJ
    Kang, YS
    Kim, CW
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 246 (01) : 238 - 242
  • [45] Protein tyrosine phosphatase 1B(PTP1B) promotes melanoma cells progression through Src activation
    Wang, Qiang
    Pan, Yuyan
    Zhao, Liping
    Qi, Fazhi
    Liu, Jiaqi
    BIOENGINEERED, 2021, 12 (01) : 8396 - 8406
  • [46] ACTIVATION OF HUMAN THYMOCYTES INDUCES THE PHOSPHORYLATION OF PROTEIN-TYROSINE-PHOSPHATASE 1C
    TRACHMAN, JD
    HUANG, J
    REEM, GH
    COMPTES RENDUS DE L ACADEMIE DES SCIENCES SERIE III-SCIENCES DE LA VIE-LIFE SCIENCES, 1995, 318 (03): : 367 - 374
  • [47] An ACTH-activated protein tyrosine phosphatase (PTP) is modulated by PKA-mediated phosphorylation
    Paz, C
    Maciel, FC
    Poderoso, C
    Gorostizaga, A
    Podestá, EJ
    ENDOCRINE RESEARCH, 2000, 26 (04) : 609 - 614
  • [48] Dissemination of human pancreatic tumor cells is mediated by src-induced phosphorylation of caveolin
    Orlichenko, L.
    Weller, S. G.
    Awoniyi, M.
    McNiven, M. A.
    PANCREAS, 2007, 35 (04) : 420 - 420
  • [49] Phosphorylation and cytoskeletal anchoring of the acetylcholine receptor by Src class protein-tyrosine kinases - Activation by rapsyn
    Mohamed, AS
    Swope, SL
    JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (29) : 20529 - 20539
  • [50] Activation of Src by Protein Tyrosine Phosphatase 1B Is Required for ErbB2 Transformation of Human Breast Epithelial Cells
    Arias-Romero, Luis E.
    Saha, Sayanti
    Villamar-Cruz, Olga
    Yip, Shu-Chin
    Ethier, Stephen P.
    Zhang, Zhong-Yin
    Chernoff, Jonathan
    CANCER RESEARCH, 2009, 69 (11) : 4582 - 4588