The mandate of this proposal is to test the hypothesis that discrete structural motifs of the proto-oncogene, Vav, may significantly contribute to PRLr-Vav interaction, Vav function, and Vav nuclear import, using the PRL-dependent Nb2 T-cell model system. Specifically, three aims are proposed, including: (1) to identify the Vav domains necessary for PRLr-Vav interaction using mutant Vav and PRLr recombinants in in vitro binding assays and confirmed in vivo by transient co-transfection; (2) to examine the association of Vav structure with function in two independent model systems by the ability of mutant Vav expression constructs to mediate PRLr signaling; and, (3) to determine the functional role of intranuclear Vav in lymphocyte proliferation and to examine its mechanism of nuclear importation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050771-03
Application #
2770551
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Smith, Philip F
Project Start
1996-09-30
Project End
2000-08-31
Budget Start
1998-09-18
Budget End
1999-08-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kline, J Bradford; Rycyzyn, Michael A; Clevenger, Charles V (2002) Characterization of a novel and functional human prolactin receptor isoform (deltaS1PRLr) containing only one extracellular fibronectin-like domain. Mol Endocrinol 16:2310-22
Clevenger, C V; Kline, J B (2001) Prolactin receptor signal transduction. Lupus 10:706-18
Kline, J B; Moore, D J; Clevenger, C V (2001) Activation and association of the Tec tyrosine kinase with the human prolactin receptor: mapping of a Tec/Vav1-receptor binding site. Mol Endocrinol 15:832-41
Clevenger, C V; Rycyzyn, M A (2000) Translocation and action of polypeptide hormones within the nucleus. Relevance to lactogenic transduction. Adv Exp Med Biol 480:77-84
Rycyzyn, M A; Clevenger, C V (2000) Role of cyclophilins in somatolactogenic action. Ann N Y Acad Sci 917:514-21
Maus, M V; Reilly, S C; Clevenger, C V (1999) Prolactin as a chemoattractant for human breast carcinoma. Endocrinology 140:5447-50
Clevenger, C V; Freier, D O; Kline, J B (1998) Prolactin receptor signal transduction in cells of the immune system. J Endocrinol 157:187-97