Protein phosphorylation on tyrosine residues plays an important role in the regulation of many physiologic processes. The dephosphorylation of these proteins is regulated by a group of protein tyrosyl phosphatases (PTPs) which have generally not been well studied. In hematopoiesis, homeostasis is maintained by the actions of growth factors and cytokines, most of which signal through protein kinases or receptor associated protein kinases. The erythropoietin receptor associates with the JAK2 tyrosine kinase upon binding of erythropoietin. Abnormalities in PTK pathways can result in hematopoietic failure or in diseases of hyperproliferation such as erythrocytosis or erythroleukemia. The overall goal of this application is to define how the SH2 containing non- transmembrane tyrosine phosphatase, SHPTP1, controls EPO receptor signal transduction and how binding of the EPO receptor to SHPTP1 controls SHPTP1 activity. The applicant proposes to define the mechanism of regulation of JAK2 by SHPTP1 in molecular detail. The exact tyrosine residue to which SHPTP1 binds in the EPO receptor will be defined. The applicant will also determine whether a familial erythrocytosis syndrome is due to abrogation of the EPO receptor/SHPTP1 interaction. He will ask if sustained JAK2 expression is sufficient to confer EPO hypersensitivity and whether the inactivation of JAK2 by SHPTP1 requires other interacting proteins. The biochemical basis for differences in specificity between SHPTP1 and its close relative, SHPTP2, in EPO receptor signalling will be determined. He will also determine whether SHPTP1 regulates signalling molecules other than JAK2 and pathways other than proliferation. The in vivo significance of the SHPTP1 EPO receptor interaction will be determined by creating transgenic mice that express EPO receptors unable to bind SHPTP1. Finally, the precise sequence determinants for phosphotyrosyl peptide binding to the amino terminal SH2 domain of SHPTP1 will be defined and the mechanism by which the SH2 domains of SHPTP1 basally repressed PTP activity will be elucidated. The results of the proposed studies may yield new insights into how PTPs contribute to the control of normal hematopoiesis and its disruption in human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050693-04
Application #
2882788
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Badman, David G
Project Start
1996-03-15
Project End
2000-02-29
Budget Start
1999-04-15
Budget End
2000-02-29
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Pao, Lily I; Lam, Kong-Peng; Henderson, Joel M et al. (2007) B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity. Immunity 27:35-48
Masiello, David; Mohi, M Golam; McKnight, Nicole C et al. (2007) Combining an mTOR antagonist and receptor tyrosine kinase inhibitors for the treatment of prostate cancer. Cancer Biol Ther 6:195-201
Pao, Lily I; Badour, Karen; Siminovitch, Katherine A et al. (2007) Nonreceptor protein-tyrosine phosphatases in immune cell signaling. Annu Rev Immunol 25:473-523
Bentires-Alj, Mohamed; Gil, Susana G; Chan, Richard et al. (2006) A role for the scaffolding adapter GAB2 in breast cancer. Nat Med 12:114-21
Nagaishi, Takashi; Pao, Lily; Lin, Sue-Hwa et al. (2006) SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms. Immunity 25:769-81
Yu, Min; Luo, Jincai; Yang, Wentian et al. (2006) The scaffolding adapter Gab2, via Shp-2, regulates kit-evoked mast cell proliferation by activating the Rac/JNK pathway. J Biol Chem 281:28615-26
Du, Zhimei; Shen, Yuhong; Yang, Wentian et al. (2005) Inhibition of IFN-alpha signaling by a PKC- and protein tyrosine phosphatase SHP-2-dependent pathway. Proc Natl Acad Sci U S A 102:10267-72
Togni, M; Swanson, K D; Reimann, S et al. (2005) Regulation of in vitro and in vivo immune functions by the cytosolic adaptor protein SKAP-HOM. Mol Cell Biol 25:8052-63
Rusanescu, Gabriel; Yang, Wentian; Bai, Ailin et al. (2005) Tyrosine phosphatase SHP-2 is a mediator of activity-dependent neuronal excitotoxicity. EMBO J 24:305-14
Mohi, M Golam; Williams, Ifor R; Dearolf, Charles R et al. (2005) Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell 7:179-91

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