The Laboratory of Dr. Renato V. Iozzo is the world-leader in proteoglycan research, focusing on the coordinated regulation of tumorigenesis, angiogenesis, and autophagy. Specifically, we study the roles of decorin and perlecan, particularly the C-terminal fragment known as endorepellin, in regulating these fundamental processes by evaluating diverse in vitro systems and novel in vivo models. We also study the pleiotropic growth factor, progranulin. Importantly, we have recently discovered that EphA2 is a functional signaling receptor for progranulin. We are currently investigating the role of progranulin / EphA2 in prostate and bladder cancer models.
Decorin is a Multifaceted Small Leucine Rich Proteoglycan that Suppresses Tumorigenesis and Evokes Autophagy
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 Processed from the C-terminus of Perlecan and Suppresses Angiogenesis and Evokes Autophagy
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 21 integrin. Upon the formation of this molecular complex, endorepellin triggers rapid dissolution of the actin cytoskeleton, VEGFA suppression, and induction of autophagy.
EphA2 is a functional signaling receptor for the growth factor progranulin
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.