The goals of our research program are to understand the fundamental principles of cell signaling in the regulation of basic cellular functions in normal cell and developmental processes and to determine how the disruption of normal signaling pathways lead to diseases such as cancer. One area of our research focuses on the role and mechanisms of focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase that is important in mediating signaling by integrins as well as some growth factor receptors, in the regulation of mammary cancer stem cells, cancer metastasis, and embryonic and tumor angiogenesis. A second area of our interests concerns the role of autophagy in breast cancer and other developmental and disease processes. Our lab initially identified FIP200 (FAK-family Interacting Protein of 200 Kd), a component of the ULK1/mAtg13/FIP200 complex essential for autophagy induction in mammalian cells, and we have recently shown the critical role of FIP200 and autophagy in tissue stem cell maintenance, neurodegeneration and mammary tumor development and progression. A third area of our studies involves the identification of signaling molecules and pathways in the regulation of cell migration and invasion and the examination of cross-talks among different pathways in these biological processes.
1982 B.S. Univ. Science and Technology of China, Hefei, China
Honors and Awards
2011 - Elected Fellow, American Association for the Advancement of Sciences
Cooper LA, Shen TL, Guan JL. Regulation of focal adhesion kinase by its amino-terminal domain through an autoinhibitory interaction. Mol Cell Biol. 2003 Nov;23(22):8030-41. PubMed PMID: 14585964; PubMed Central PMCID: PMC262338.
Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. (2005). T.-L. Shen, A. Park, A. Alcaraz, X. Peng, I. Jang, P. Koni, R. Flavell, H. Gu and J.-L. Guan. J. Cell Biol. 169: 941-952.
The mechanisms of the cell cycle arrest by FIP200 in human breast cancer cells. (2005). Z. Melkoumian, X. Peng, B. Gan, X. Wu and J.-L. Guan. Cancer Research. 65, 6676-6684.
Identification of FIP200 interaction with TSC1-TSC2 complex and its role in regulation of cell size control. (2005). B. Gan, Z. Melkoumian, X. Wu, K.-L. Guan, and J.-L. Guan. J. Cell Biol. 170, 379-389.
FAK-mediated Src phosphorylation of Endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation. (2005). X. Wu, B. Gan, Y. Yoo and J.-L. Guan. Dev. Cell. 9, 185-196. (Featured article in this issue).
Inactivation of FAK in cardiomyocytes promotes cardiac eccentric hypertrophy and fibrosis in mice. (2006). X. Peng, M. S. Kraus, H. Wei, T.-L. Shen, R. Pariaut, A. Alcaraz, G. Ji, L. Cheng, Q. Yang, M. I. Kotlikoff, J. Chen, K. Chien, H. Gu and J.-L. Guan. J. Clin. Invest. 116: 217-227.
Regulation of RNA polymerase II-dependent transcription by N-WASP and its nuclear binding partners. (2006). X. Wu, Y.Yoo, N. N. Okuhama, P. W. Tucker, G. Liu and J.-L. Guan. Nat. Cell Biol. 8: 756-763. (Also see NCB News and Views p650-651 in the same issue; and Leading Edge: Cell 126, 431-433, 2006).
Role of FIP200 in cardiac and liver development and its regulation of TSC-mTOR and TNFa signaling pathways. (2006). B. Gan, X. Peng, T. Nagy, A. Alcaraz, H. Gu and J.-L. Guan. J. Cell Biol. 175: 121-133.
Y.Yoo, X. Wu and J.-L. Guan. A novel role of the actin-nucleating Arp2/3 complex in the regulation of RNA polymerase II-dependent transcription. (2007). J. Biol. Chem. 282: 7616-7623.
T. Nagy, H. Wei, T.-L. Shen, X. Peng, C.-C. Liang, B. Gan, and J.-L. Guan. Mammary Epithelial-Specific Deletion of the Focal Adhesion Kinase Gene Leads to Severe Lobulo-Alveolar Hypoplasia and Secretory Immaturity of the Murine Mammary Gland (2007). J. Biol. Chem. 282: 31766-31776.
X. Peng, X. Wu, J. E. Druso, H. Wei, A. Y.-J. Park, M. S. Kraus, A. Alcaraz, J. Chen, S. Chien, R. A. Cerione and J.-L. Guan. Cardiac developmental defects and spontaneous eccentric right ventricular hypertrophy in cardiomyocyte FAK conditional knockout mice. (2008). Proc. Natl. Acad. Sci. USA. 105: 6638-6643.
B. Gan and J.-L. Guan. FIP200, a key signaling node to coordinately regulate various cellular processes. (2008). Cellular Signalling. 20: 787-794.
S. M. Weis, S.-T. Lim, K. M. Lutu-Fuga, L. A. Barnes, X.L. Chen, J. R. Göthert, T.-L. Shen, J.-L. Guan, D. D. Schlaepfer and D.A. Cheresh. Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK (2008). J. Cell Biol. 181: 43-50.
T. Hara, A. Takamura, C. Kishi, S. Iemura, T. Natsume, J.-L. Guan and N. Mizushima. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells (2008). J. Cell Biol. 181: 497-510.
A. Bechara, H. Nawabi, F. Moret, A. Yaron, E. Weaver, M. Bozon, K. Abouzid, J.-L.Guan, M. Tessier-Lavigne, V. Lemmon, V. Castellani. FAK-MAPK-dependent adhesion disassembly downstream of L1 contributes to semaphorin3A-induced collapse (2008). EMBO J. 27:1549-1562.
M. Luo, H. Fan, T. Nagy, H. Wei, C. Wang, S. Liu, M. S. Wicha and J.-L. Guan. Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells (2009). Cancer Res. 69: 466-474.
H. Wei, B.Gan, X. Wu and J.-L. Guan. Inactivation of FIP200 leads to inflammatory skin disorder, but not tumorigenesis, in conditional knockout mouse models (2009). J. Biol. Chem. 284, 6004-6013.
J. Zhao and J.-L. Guan. Signal Transduction by Focal Adhesion Kinase in Cancer (2009). Cancer and Metastasis Reviews series. In press.
Guan JL. Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer. IUBMB Life. 2010 Apr;62(4):268-76. Review. PubMed PMID: 20101634; PubMed Central PMCID: PMC2848709.
F. Liu, J. Lee, H. Wei, O. Tanabe, J. D. Engel, S. J. Morrison and J.-L. Guan. FIP200 is required for the cell-autonomous maintenance of fetal hematopoietic stem cells (2010). Blood. 116: 4806-4814.
H. Fan and J.-L. Guan. Compensatory function of Pyk2 in the promotion of FAK-null mammary cancer stem cell tumorigenicity and metastatic activity (2011). J. Biol. Chem. 286: 18573-18282.
D. Wang, M. A. Olman, J. Stewart, Jr., R. Tipps, P. Huang, P. W. Sanders, E. Toline, R. A. Prayson, J. Lee, R. J. Weil, C. A. Palmer, G. Y. Gillespie, W. Liu, R. O. Pieper, J.-L. Guan and C. L. Gladson. Downregulation of FIP200 Induces Apoptosis of Glioblastoma Tumor Cells and Microvascular Endothelial Cells by Enhancing Pyk2 Activity (2011). PLoS One 6: e19629.
S. Kageyama, H. Omori, T. Saitoh, T. Sone, J.-L. Guan, S. Akira, F. Imamoto, T. Noda and T. Yoshimori. The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella (2011). Mol. Biol. Cell. 20: 1981-1991. 2011 Apr 27. [Epub ahead of print]
J. Seong, M. Ouyang, T. Kim, J. Sun, P.-C. Wen, S. Lu, N. M. Llewellyn, D. D. Schlaepfer, J.-L. Guan, S. Chien, Y. Wang. Detect FAK Activations at Membrane Microdomains by FRET (2011). Nature Communications. Accepted.
H Wei, S. Wei, B. Gan, X. Peng, W. Zou and J.-L. Guan. Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis (2011). Genes Dev, Accepted.
H. Bae and J.-L. Guan. Inactivation of FIP200 leads to defective DNA damage repair and increased sensitivity to DNA break-induced cell death in mouse embryonic fibroblasts (2011). Mol. Cancer Res. Accepted.
F. Liu and J.-L. Guan. FIP200, an essential component of mammalian autophagy is indispensible for fetal hematopoiesis. (2011). Autophagy 7: 229-230.
X. Zhao and J.-L. Guan. Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. (2011). Advanced Drug Delivery Reviews, In Press. DOI: 10.1016/j.addr.2010.11.001