Although it is well established that receptor-mediated elevation in diacylglycerol (DAG) levels leads to activation of protein kinase C (PKC), a novel receptor for this lipophilic second messenger and its analogs, the phorbol ester tumor promoters, was recently discovered: chimaerin. In contrast to PKC, N-chimaerin does not possess a kinase domain. Its catalytic domain has high homology to BCR (breakpoint cluster region), a protein involved in Philadelphia chromosome translocation in chronic myelogenous leukemia. Like BCR, n-chimaerin has GTPase-activating protein (GAP) activity for the p21Rac, a small GTP-binding protein which plays a central role in cytoskeletal structure, gene transcription, cell growth and malignant transformation. The expansion of the chimaerin family with the cloning of new isoforms (a1- or """"""""n-"""""""",a2-,b1-,andb2-chimaerins) indicates that a high degree of complexity may exist in the downstream pathways triggered by DAG. The fact that the a2- and b2-chimaerins possess SH2 motifs on their structure predicts that these chimaerin isoforms may associate with tyrosine phosphorylated proteins which may regulate their activity or localization, therefore suggesting crosstalk between different signaling pathways. The overall goal of this proposal is to evaluate whether the second messenger DAG and the phorbol ester tumor promoters regulate the chimaerin activity in addition to that of PKC, and to determine the biological consequences of the activation of this pathway in the cell.
In Specific Aim 2, he will identify proteins that associate to chimaerins. The SH2 domains of a2- and 2-chimaeri withphosphotyrosine proteins. We will also study whether translocation induced by phorbol esters leads to the association of chimaerins with specific targets or anchoring proteins.
In Specific Aim 3 he will focus on the biological roles of chimaerins. Our hypothesis is that chimaerins may affect those responses mediated by p21Rac, and therefore affect cell growth, malignant transformation, and cell morphology.Dr. Kazanietz's research has the potential for defining new """"""""PKC independent"""""""" pathways for the phorbol ester tumor promoters and DAG, and hopefully will yield new insights into the events controlling malignant transformation. The characterization of the targets for the phorbol esters would be valuable to clarify their biological actions and also to unravel pathways involved in the mechanisms of carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074197-02
Application #
2748931
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Okano, Paul
Project Start
1997-09-30
Project End
2002-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Dipaolo, Brian C; Davidovich, Nurit; Kazanietz, Marcelo G et al. (2013) Rac1 pathway mediates stretch response in pulmonary alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 305:L141-53
Gutierrez-Uzquiza, Alvaro; Colon-Gonzalez, Francheska; Leonard, Thomas A et al. (2013) Coordinated activation of the Rac-GAP ?2-chimaerin by an atypical proline-rich domain and diacylglycerol. Nat Commun 4:1849
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Wang, Hongbin; Kazanietz, Marcelo G (2010) p23/Tmp21 differentially targets the Rac-GAP beta2-chimaerin and protein kinase C via their C1 domains. Mol Biol Cell 21:1398-408
Griner, Erin M; Caino, M Cecilia; Sosa, Maria Soledad et al. (2010) A novel cross-talk in diacylglycerol signaling: the Rac-GAP beta2-chimaerin is negatively regulated by protein kinase Cdelta-mediated phosphorylation. J Biol Chem 285:16931-41
Notcovich, Cintia; Diez, Federico; Tubio, Maria Rosario et al. (2010) Histamine acting on H1 receptor promotes inhibition of proliferation via PLC, RAC, and JNK-dependent pathways. Exp Cell Res 316:401-11

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