v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the oncogenic growth of cells.
We investigated the effect of cell transformation by v-src on the expression and tyrosine phosphorylation of SHPS-1, a putative docking protein for SHP-1 and SHP-2. We found that transformation by v-src virtually inhibited the SHPS-1 expression at mRNA level. While nontransforming Src kinases including c-Src, nonmyristoylated forms of v-Src had no inhibitory effect on SHPS-1 expression, transforming Src kinases including wild-type v-Src and chimeric mutant of c-Src bearing v-Src SH3 substantially suppressed the SHPS-1 expression. In cells expressing temperature sensitive mutant of v-Src, suppression of the SHPS-1 expression was temperature-dependent. In contrast, tyrosine phosphorylation of SHPS-1 was rather activated in cells expressing c-Src or nonmyristoylated forms of v-Src. SHPS-1 expression in SR3Y1 was restored by treatment with herbimycin A, a potent inhibitor of tyrosine kinase, or by the expression of dominant negative form of Ras. Contrary, active form of Mekl markedly suppressed SHPS-1 expression. Finally, overexpression of SHPS-1 in SR3Y1 led to the drastic reduction of anchorage independent growth of the cells. Taken together, our results suggest that the suppression of SHPS-1 expression is a pivotal event for cell transformation by v-src, and the Ras-MAP kinase cascade plays a critical role in the suppression.
Machida
K
K
Department of Molecular Pathogenesis, Nagoya University School of Medicine, Japan.
Matsuda
S
S
Yamaki
K
K
Senga
T
T
Thant
A A
AA
Kurata
H
H
Miyazaki
K
K
Hayashi
K
K
Okuda
T
T
Kitamura
T
T
Hayakawa
T
T
Hamaguchi
M
M
D016475:3T3 Cells; D000215:Acylation; D000818:Animals; D000943:Antigens, Differentiation; D001358:Avian Sarcoma Viruses / Q000235:genetics / Q000502:physiology*; D016227:Benzoquinones; D002448:Cell Adhesion; D002455:Cell Division; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D015967:Gene Expression Regulation, Viral; D016391:Genes, src; D006207:Half-Life; D047029:Lactams, Macrocyclic; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D019814:Myristic Acid / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D015688:Oncogene Protein pp60(v-src) / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017828:Rifabutin / Q000031:analogs & derivatives; D014162:Transfection; D018631:ras Proteins / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology
D000943:Antigens, Differentiation; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; C501922:Sirpa protein, mouse; D011809:Quinones; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C501924:Sirpa protein, rat; D019814:Myristic Acid; D017828:Rifabutin; C020754:herbimycin; D015688:Oncogene Protein pp60(v-src); D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D018631:ras Proteins