• Title Associate Professor
  • Education PhD: Ludwig Maximilians University, Munich, Germany
    Postdoctoral Training: The Rockefeller University
  • Office K123C
  • Phone 617-638-4376
  • Area of Interest cancer cell biology, lysyl oxidase, breast cancer stroma

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.

  1. 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 Feb 11. PMID: 26867768.
    View in: PubMed
  2. 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.
    View in: PubMed
  3. 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.
    View in: PubMed
  4. 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.
    View in: PubMed
  5. 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.
    View in: PubMed
  6. 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.
    View in: PubMed
  7. 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.
    View in: PubMed
  8. 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.
    View in: PubMed
  9. Yu Z, Sato S, Trackman PC, Kirsch KH, Sonenshein GE. Blimp1 activation by AP-1 in human lung cancer cells promotes a migratory phenotype and is inhibited by the lysyl oxidase propeptide. PLoS One. 2012; 7(3):e33287. PMID: 22438909.
    View in: PubMed
  10. Bais MV, Nugent MA, Stephens DN, Sume SS, Kirsch KH, Sonenshein GE, Trackman PC. Recombinant lysyl oxidase propeptide protein inhibits growth and promotes apoptosis of pre-existing murine breast cancer xenografts. PLoS One. 2012; 7(2):e31188. PMID: 22363577.
    View in: PubMed

Complete list can be found at BU Profiles

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