Expression of the insulin-like growth factor-I (IGF-I) receptor (IGF-IR) is essential to allow malignant cell transformation to occur in response to various oncogenic stimuli. Most oncogenes including SV40 T antigen, Ras, Raf, bovine papilloma virus, or overexpressed PDGF or EGF receptors fail to transform cells lacking the IGF-I receptor, which can be overcome by IGF-I receptor expression. We propose to test the hypothesis that an unknown mediator which associates with and is situated downstream of the IGF-I receptor is essential in this transformation competence pathway. This mediator should provide a target for medical therapies to interfere with a variety of cell transforming factors. My colleagues and I have recently identified a candidate Pro-rich, PH and SH2 domain-containing Signaling Mediator in our laboratory, termed PSM/mSH2-B, which will be the focus of this proposal. A potential role for PSM as a cell transformation mediator and downstream partner of the IGF- I receptor is supported by six lines of evidence from our Preliminary Studies: 1.) PSM displays a domain structure which is typical for many receptor tyrosine kinase signaling mediators. 2.) Ligand activation of several mitogenic receptor tyrosine kinases results in their association with PSM. 3.) PSM specifically binds to the IGF-I receptor carboxyl terminus (upon receptor activation), a region which has been implicated in the tumorigenic potential of this receptor. 4.) Microinjection of the dominant-negative PSM SH2 domain interferes with the mitogenic response of fibroblasts to IGF-I and other growth factor stimuli. 5.) Introduction of cell-permeable antennapedia fusion peptides containing a putative PSM SH3 domain binding region inhibits IGF-I-mediated mitogenesis in fibroblasts. 6.) Microinjection of the PSM SH2 domain also interferes with the transformed phenotype of spontaneously transformed and metastatic fibroblasts and partially restores their normal phenotype. Our goals are to establish the molecular mechanism of PSM action and its cellular role in IGF-I receptor mitogenesis and tumorigenesis, as well as to define strategies to interfere with its functions.
Our Specific Aims are to: I. Characterize the interaction of PSM with the IGF-I receptor. II. Define other cellular partners of PSM and the involved interactions. III. Establish the role of PSM and its domains in IGF-IR-mediated mitogenesis and in cell transformation by interfering (dominant negative) and PSM overexpression strategies. These studies will elucidate an unexplored mechanism in a key mitogenic signaling pathway which is shared by many cell types.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077873-04
Application #
6513225
Study Section
Endocrinology Study Section (END)
Program Officer
Spalholz, Barbara A
Project Start
1999-06-01
Project End
2003-10-31
Budget Start
2002-04-01
Budget End
2003-10-31
Support Year
4
Fiscal Year
2002
Total Cost
$67,557
Indirect Cost
Name
Wayne State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Zhang, Manchao; Deng, Youping; Tandon, Ruchi et al. (2008) Essential role of PSM/SH2-B variants in insulin receptor catalytic activation and the resulting cellular responses. J Cell Biochem 103:162-81
Deng, Youping; Zhang, Manchao; Riedel, Heimo (2008) Mitogenic roles of Gab1 and Grb10 as direct cellular partners in the regulation of MAP kinase signaling. J Cell Biochem 105:1172-82
Zhang, Manchao; Deng, Youping; Riedel, Heimo (2008) PSM/SH2B1 splice variants: critical role in src catalytic activation and the resulting STAT3s-mediated mitogenic response. J Cell Biochem 104:105-18
Deng, Youping; Xu, Hu; Riedel, Heimo (2007) PSM/SH2-B distributes selected mitogenic receptor signals to distinct components in the PI3-kinase and MAP kinase signaling pathways. J Cell Biochem 100:557-73
Riedel, Heimo (2004) Grb10 exceeding the boundaries of a common signaling adapter. Front Biosci 9:603-18
Lim, Mei A; Riedel, Heimo; Liu, Feng (2004) Grb10: more than a simple adaptor protein. Front Biosci 9:387-403
Deng, Youping; Bhattacharya, Sujoy; Swamy, O Rama et al. (2003) Growth factor receptor-binding protein 10 (Grb10) as a partner of phosphatidylinositol 3-kinase in metabolic insulin action. J Biol Chem 278:39311-22
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Riedel, H; Yousaf, N; Zhao, Y et al. (2000) PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis. Oncogene 19:39-50