Regulation of Cell Function by Matricellular Hevin

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DESCRIPTION (provided by applicant): This application addresses the structure, regulation, and function of the matricellular protein hevin, a relatively understudied member of the SPARC (secreted protein acidic and rich in cysteine) family of secreted glycoproteins. Also known as SC-1, MAST 9, SPARC-like 1, and ECM2, hevin has been described as a tumor-suppressor gene that also features prominently in the development and morphogenesis of certain tissues. In vitro, hevin has demonstrated deadhesive activity and enhancement of endothelial monolayer permeability, effects mediated in part by its diminishment of focal adhesion complexes in these cells. Despite recent provocative data regarding the association of hevin with tumor cell proliferation and/or metastasis, mechanisms accounting for these activities have remained elusive. We propose that hevin acts as a deadhesive, anti-proliferative matricellular protein that suppresses the growth of certain tumors via its modulation of tumor-stromal cell interactions. Accordingly, experiments described in this proposal test 3 hypotheses, based on our current understanding of hevin structure and function: 1) Selective deadhesion, cell-cycle inhibition, and regulation of extracellular matrix (ECM) production control specific aspects of tissue repair/angiogenesis and tumor progression. In Aim 1, we examine mechanisms governing these activities, as well as a cell-surface receptor/binding partner for hevin. 2) Regulation of the hevin gene and its posttranslational modifications are critical to our understanding of how hevin might act as a tumor suppressor. Aim 2 addresses these parameters in the context of tumor cell growth and angiogenesis in vitro. 3) There is both tissue tumor-specific and protein domain-specific compensation between hevin and its homolog SPARC, but hevin also has unique functions. Aim 3 features mice with targeted deletions of SPARC, hevin, and SPARC plus hevin, coupled with domain swaps between the two proteins, to evaluate the effect of hevin on tumor growth and metastasis in vivo. From an elucidation of molecular mechanisms by which hevin exerts its various regulatory activities on normal and tumor cells in vitro, we predict a better understanding of tumor-host stromal cell interactions in vivo, and the role of the matricellular protein hevin therein.