Ion studies and mouse colony upkeep, and Xin Sun (UW-Madison) for giving the mouse Noggin cDNA and Gremlin knockout mice. This work was supported by the following Peterson Lab grants: NIH P50 DK065303, NIH R37 ES01332, F32 ES014284, and F31 HD049323 and Bushman Lab grants: NIH P50 DK052687, NIH O’Brien DK065303, and DOD W81XWH.
NIH Public AccessAuthor ManuscriptcIAP-2 Molecular Weight Biochemistry. Author manuscript; obtainable in PMC 2009 Chk2 web October 28.Published in final edited kind as: Biochemistry. 2008 October 28; 47(43): 111741183. doi:10.1021/bi8013938.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptDiverse Cell Signaling Events Modulated by PerlecanJohn M. Whitelock, James Melrose and Renato V. Iozzo, Graduate College of Biomedical Engineering, University of New South Wales, Kensington, Australia �Raymond Purves Research Laboratories, Institute of Bone and Joint Analysis, Kolling Institute of Healthcare Research, University of Sydney, Royal North Shore Hospital, St. Leonards, Australia Department of Pathology, Anatomy and Cell Biology along with the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PennsylvaniaAbstractPerlecan is a ubiquitous pericellular proteoglycan ideally placed to mediate cell signaling events controlling migration, proliferation and differentiation. Its control of growth element signaling ordinarily includes interactions together with the heparan sulfate chains covalently coupled for the protein core’s Nterminus. Nonetheless, this modular protein core also binds with comparatively higher affinity to numerous development variables and surface receptors, thereby stabilizing cell-matrix hyperlinks. This critique will concentrate on perlecan/growth issue interactions and describe recent advances in our understanding of this highlyconserved proteoglycan in the course of development, cancer growth and angiogenesis. The pro-angiogenic capacities of perlecan that involve proliferative and migratory signals in response to bound development components will probably be explored, too because the anti-angiogenic signals resulting from interactions between the C-terminal domain known as endorepellin and integrins that handle cell adhesion for the extracellular matrix. These two somewhat diametrically-opposed roles will likely be discussed in light of new data emerging from many fields which converge on perlecan as a key regulator of cell growth and angiogenesis. Perlecan was initially isolated in 1980 by Hassell and coworkers from the Engelbreth-HolmSwarm sarcoma, a basement membrane-secreting tumor, and was quickly demonstrated to be expressed also in the cell surface of human colon carcinoma cells (1). In spite of their differential expression, the two molecules were shown to possess biosynthetic and immunological similarities. As a result of its substantial size –the mRNA encoding perlecan is 15 kb–it took over a decade of efforts to finish the cDNA cloning from the full-length mouse perlecan, followed by the comprehensive structure from the human counterpart, its chromosomal mapping, and its genomic organization (2). The eponym “perlecan” derives from its ultrastructural appearance of “beads on a string”, a feature attributable for the various globular domains interspersed among much more linear structures (1). Perlecan is composed of five distinct domains with homology to development components and to protein modules involved in lipid metabolism, cell adhesion, and homotypic and heterotypic interactions (3). Notably, the N-terminal domain I consists of 3 attachment s.