|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
||||||||||||||||||||||||
|
|
|
|
||||||||||||||||||||||
|
|
|
|
||||||||||||||||||||||
|
|
||||||||||||||||||||||||
|
|
|
|
|
|
|
|
|
|
||||||||||||||||
|
|
|
|
|
|
|
|
|
|||||||||||||||||
|
|
|
|
|
|
|
|
||||||||||||||||||
|
|
|
|
|
|
|
|
||||||||||||||||||
|
|
|
|
||||||||||||||||||||||
|
|
||||||||||||||||||||||||
|
Research Description: The syndecans, a family of four cell surface receptors (heparan sulfate proteoglycans), are cell adhesion receptors and regulators of signaling by growth factors/growth factor receptors and cell adhesion receptors, especially integrins. They are expressed on all adherent cells and regulate cell behavior during development and cancer. Our major focus is syndecan-1, which is abundant on epithelial cells and appears necessary for the maintenance of normal epithelial cell adhesion and morphology. Part of our current work focuses on the regulatory roles of the syndecan-1 core protein on breast carcinoma cells. Our model is that syndecan-1 is a critical regulator of cell proliferation and invasion of mammary carcinoma cells. Our data indicate that the proliferation and morphogenesis of either normal or tumorigenic breast epithelial cells in three-dimensional matrices is exquisitely dependent on syndecan-1. Part of this regulation traces to syndecan regulation of signaling downstream of the _3b1 integrin, which controls the polarity vs. invasion of the cells. A second finding is that syndecan-1 is a potent regulator of the _vb3 integrin; this integrin is essential for extravasation of blood-borne metastatic cells from the blood system and their invasion into a target tissue , and is also critical for the proliferation and survival of the tumor cells at that site. We now know that the activation and signaling by this integrin is dependent on the extracellular domain of syndecan-1. We are currently examining how the regulation of these integrins occurs, what signaling mechanisms are involved, and how we can disrupt this activation and therefore control breast carcinoma cell metastasis and survival. A second part of the breast carcinoma cell project focuses on another integrin, the _6b4 integrin. This integrin has been shown to be a critical player in carcinoma invasion. When “activated” by phosphorylation from the EGF receptor or HGF receptor (c-met), the b4 subunit activates PI-3 kinase signaling which leads to active cell migration. We have new evidence that the syndecan-1 cytoplasmic domain interacts with the cytoplasmic domain of the b4 subunit and is necessary for this invasive activity. We are currently examining the effects of mutations in the syndecan and b4 integrin cytoplasmic domains on the b4-mediated cell invasion (Figure 1). In addition to the activities of the proteins themselves, the heparan sulfate chains on the syndecans bind to “heparin”-binding growth factors and morphogens, including members of the fibroblast growth factor (FGF) family. The FGFs are important in cell growth, wound healing, angiogenesis, and cell differentiation. These behaviors are triggered by FGFs bound in a cell surface complex with syndecans and FGF-specific receptor tyrosine kinases. Both the FGF and its receptor tyrosine kinase bind to heparan sulfate chains, and we are now showing that the specific pattern of sulfation in the heparan sulfate chain regulates which FGF and receptor pairs can interact. Our model is that the cell controls FGF signaling activity at its surface by altering the sulfation pattern of the heparan sulfate chains that it expresses. Our new data support this model as they demonstrate that the sulfation pattern in heparan sulfate changes rapidly during early mouse development where the FGFs have important developmental roles. We are currently focusing on endothelial cells, which rely on several FGFs for vasculogenesis during development and angiogenesis during wound healing and tumor formation, to identify specific sulfation domains within the heparan sulfate chains that regulate the FGF activity (Figure 2).
Recent invited talks:
Current Lab Members:
|
