Mitogens such as growth factors, depend on the nature of target cell, can induce cell migration, differentiation, apoptosis or survival, as well as stimulation or inhibition of cell proliferation. The regulation of growth factor signaling pathway is tightly regulated in both time and space, however corruption along this pathway can lead to the course of oncogenic transformation and tumorigenesis. Remarkable progress has been made in understanding steps in regulation of mitogen-induced cellular reactions. Nonetheless, there is still a gap in our knowledge concerning the intracellular mechanisms which regulation cellular responses toward mitogenic stimuli. Effort has been made to define the steps of intracellular kinase cascades used for cells to transfer mitogenic signal from the cell surface to the nucleus. Central to such kinase cascades are the group of serine/threonine kinases comprising the MAP kinase family. Here we propose to study the role of one group of MAP kinase, the BMK1 group, because the BMK1 pathway has been implicated in mitogens induced immediate early genes. The major focus here is to analyze the structure/function of the components in the activating module of BMK1 pathway and to characterize the regulatory mechanism and biological role of BMK1 pathway in heregulin-induced breast cancer cells activation. To do this we will utilize a combination of biochemical, immunologic and molecular biologic approaches. Implicit in the proposed studies is the development of new approaches to intervene in cancer-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079871-02
Application #
6376972
Study Section
Pathology B Study Section (PTHB)
Program Officer
Blair, Donald G
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$239,355
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Deng, Xianming; Elkins, Jonathan M; Zhang, Jinwei et al. (2013) Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones. Eur J Med Chem 70:758-67
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Chen, Runqiang; Yang, Qingkai; Lee, Jiing-Dwan (2012) BMK1 kinase suppresses epithelial-mesenchymal transition through the Akt/GSK3? signaling pathway. Cancer Res 72:1579-87
Deng, Xianming; Dzamko, Nicolas; Prescott, Alan et al. (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat Chem Biol 7:203-5
Yang, Qingkai; Lee, Jiing-Dwan (2011) Targeting the BMK1 MAP kinase pathway in cancer therapy. Clin Cancer Res 17:3527-32
Yang, Qingkai; Deng, Xianming; Lu, Bingwen et al. (2010) Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein. Cancer Cell 18:258-67
Chen, Run-Qiang; Yang, Qing-Kai; Lu, Bing-Wen et al. (2009) CDC25B mediates rapamycin-induced oncogenic responses in cancer cells. Cancer Res 69:2663-8
Chen, Yanling; Lu, Bingwen; Yang, Qingkai et al. (2009) Combined integrin phosphoproteomic analyses and small interfering RNA--based functional screening identify key regulators for cancer cell adhesion and migration. Cancer Res 69:3713-20
Chen, Run-Qiang; Yang, Qing-Kai; Chen, Yan-Ling et al. (2009) Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia. J Biol Chem 284:16752-8
Zhu, J-H; Chen, R; Yi, W et al. (2008) Protein tyrosine phosphatase PTPN13 negatively regulates Her2/ErbB2 malignant signaling. Oncogene 27:2525-31

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