Decorin is a small leucine rich proteoglycan initially characterized for regulating collagen fibrillogenesis. However, this paradigm changed upon the discovery that soluble decorin directly binds, with high affinity, to a plethora of cell surface receptor tyrosine kinases that are richly expressed by the tumor microenvironment and parenchyma. Upon receptor engagement, decorin briefly activates the receptor resulting in a multitude of intracellular signaling events before triggering receptor internalization and lysosomal degradation. Investigating the downstream transduction pathways revealed key molecular targets underpinning decorin-mediated cell cycle arrest and tumorigenic and angiogenic suppression. Recently, we found that decorin evokes a protracted autophagic program in endothelial cells mitochondrial autophagy in tumor cells. Collectively, our lab is defining the role of an exclusively extracellular component in regulating crucial intracellular functions to combat tumorigenesis. 

Endorepellin is proteolytically released from the C-terminus of perlecan and conveys potent anti-angiogenic and pro-autophagic properties that are specific for endothelial cells. Perlecan is a large, modular heparan sulfate proteoglycan that functions as an integral basement membrane component in a diverse array of tissues. Intriguingly, the parent molecule, perlecan, is pro-angiogenic, and likely anti-autophagic. Endorepellin is a “dual receptor antagonist” that acts as a molecular tether for simultaneous ligation of VEGFR2 and the 21 integrin. Upon the formation of this molecular complex, endorepellin triggers rapid dissolution of the actin cytoskeleton, VEGFA suppression, and induction of autophagy. 

Discovered as a binding partner of endorepellin/domain V of perlecan that co-localizes in the perivascular basement membranes, a functional signaling receptor for progranulin has remained elusive. However, we have very recently identified the receptor tyrosine kinase EphA2 as an authentic signaling receptor for progranulin. This discovery is congruent with the known biological effects of progranulin such as the activation of MAPK and Akt pathways. Progranulin also stimulates capillary morphogenesis downstream of EphA2 as well as the ability to auto-regulate its own expression.