My laboratory is working on delineating molecular mechanisms that are important for tumor initiation and progression, with a specific focus on the expanding family of cytoplasmic adapter proteins. We are investigating the participation of p130Cas family proteins in growth regulation in cancers of the mammary gland. We have developed a transgenic animal model expressing a dominant-interfering p130Cas to investigate the role(s) of this molecule in normal mammary development and in breast cancer in vivo induced by aberrant expression of ErbB and Src family tyrosine kinases. Recently we have identified another adapter that associates with the SH3 domain of p130Cas, named CD2AP/CMS. We have found that CD2AP associates with the ubiquitin ligase c-Cbl in response to growth factors stimulation, and with F-actin. Moreover, we showed that CD2AP forms heterotypic complexes with its family member CIN85, and that both molecules bundle F-actin in vitro. Our current work with CD2AP is focused on its roles in growth factor signaling, cell adhesion and migration, and in growth factor-mediated remodeling of the actin cytoskeleton. In a collaborative effort with Dr. Sonenshein and Dr. Trackman, we are working on elucidating the mechanism of action of lysyl oxidase (LOX) on inhibition of Ras-mediated transformation. We have demonstrated that the propeptide region of LOX attenuates Ras- and Her-2/neu-dependent breast cancers in vitro and in xenograft models. Studies are in the progress to elucidate the mechanism of this inhibition. We are also investigating the activation of cancer associated fibroblasts (CAF) and their role in breast cancer progression. Long-term goals are to determine the potential for use the propeptide or derivatives in treatment of patients with Her-2/neu or Ras-mediated breast disease.
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- Ludwig-Maximilians-Universität München, PhD
- Published on 3/22/2018
de la Cueva A, Emmerling M, Lim SL, Yang S, Trackman PC, Sonenshein GE, Kirsch KH. A Polymorphism in the Lysyl Oxidase Propeptide Domain Accelerates Carcinogen-induced Cancer. Carcinogenesis. 2018 Mar 22. PMID: 29579155.
- Published on 4/25/2017
Sánchez-Morgan N, Kirsch KH, Trackman PC, Sonenshein GE. UXT Is a LOX-PP Interacting Protein That Modulates Estrogen Receptor Alpha Activity in Breast Cancer Cells. J Cell Biochem. 2017 Aug; 118(8):2347-2356. PMID: 28106301.
- Published on 2/11/2016
Kumbrink J, de la Cueva A, Soni S, Sailer N, Kirsch KH. A truncated phosphorylated p130Cas substrate domain is sufficient to drive breast cancer growth and metastasis formation in vivo. Tumour Biol. 2016 Aug; 37(8):10665-73. PMID: 26867768.
- Published on 8/20/2015
Rouka E, Simister PC, Janning M, Kumbrink J, Konstantinou T, Muniz JR, Joshi D, O'Reilly N, Volkmer R, Ritter B, Knapp S, von Delft F, Kirsch KH, Feller SM. Differential Recognition Preferences of the Three Src Homology 3 (SH3) Domains from the Adaptor CD2-associated Protein (CD2AP) and Direct Association with Ras and Rab Interactor 3 (RIN3). J Biol Chem. 2015 Oct 16; 290(42):25275-92. PMID: 26296892.
- Published on 3/24/2015
Kumbrink J, Soni S, Laumbacher B, Loesch B, Kirsch KH. Identification of Novel Crk-associated Substrate (p130Cas) Variants with Functionally Distinct Focal Adhesion Kinase Binding Activities. J Biol Chem. 2015 May 8; 290(19):12247-55. PMID: 25805500.
- Published on 10/22/2013
Sato S, Zhao Y, Imai M, Simister PC, Feller SM, Trackman PC, Kirsch KH, Sonenshein GE. Inhibition of CIN85-mediated invasion by a novel SH3 domain binding motif in the lysyl oxidase propeptide. PLoS One. 2013; 8(10):e77288. PMID: 24167568.
- Published on 8/23/2013
Chen CH, Ho YC, Ho HH, Chang IC, Kirsch KH, Chuang YJ, Layne MD, Yet SF. Cysteine-rich protein 2 alters p130Cas localization and inhibits vascular smooth muscle cell migration. Cardiovasc Res. 2013 Dec 1; 100(3):461-71. PMID: 23975851.
- Published on 7/15/2013
Chakrabarti P, Kim JY, Singh M, Shin YK, Kim J, Kumbrink J, Wu Y, Lee MJ, Kirsch KH, Fried SK, Kandror KV. Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Mol Cell Biol. 2013 Sep; 33(18):3659-66. PMID: 23858058.
- Published on 7/3/2013
Zhao Y, Kumbrink J, Lin BT, Bouton AH, Yang S, Toselli PA, Kirsch KH. Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression. Carcinogenesis. 2013 Dec; 34(12):2880-90. PMID: 23825155.
- Published on 12/31/2012
Kumbrink J, Kirsch KH. p130Cas acts as survival factor during PMA-induced apoptosis in HL-60 promyelocytic leukemia cells. Int J Biochem Cell Biol. 2013 Mar; 45(3):531-5. PMID: 23287717.
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