dally, a Drosophila glypican, controls cellular responses to the TGF-β-related morphogen, Dpp

Abstract

Decapentaplegic (Dpp) is a Drosophila member of the Transforming Growth Factor-beta (TGF-beta)/Bone Morphogenetic Protein (BMP) superfamily of growth factors. Dpp serves as a classical morphogen, where concentration gradients of this secreted factor control patterning over many cell dimensions. Regulating the level of Dpp signaling is therefore critical to its function during development. One type of molecule proposed to modulate growth factor signaling at the cell surface are integral membrane proteoglycans. We show here that division abnormally delayed (dally), a Drosophila member of the glypican family of integral membrane proteoglycans is required for normal Dpp signaling during development, affecting cellular responses to this morphogen. Ectopic expression of dally+ can alter the patterning activity of Dpp, suggesting a role for dally+ in modulating Dpp signaling strength. These findings support a role for members of the glypican family in controlling TGF-beta/BMP activity in vivo by affecting signaling at the cell surface.

APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer

“…Glypicans are a family of proteoglycans, comprising two members in drosophila (Dally and Dally-like-protein, Dlp), that have expanded to six paralogous orthologs in mammals (Gpc1-6) [41] . Dally and Dlp have been implicated in the regulation of most known signal transduction pathways, including WNT, TGFβ, IGF, FGF, VEGF, Hh, HGF, and BMP [8,[21][22][23][24][25][26][27][28][29][30][31][32] . Most current models for Glypican function indicate that these proteoglycans, when anchored to the cell surface, act to potentiate receptor-ligand interactions.…”

“…These transcriptional pathways reside downstream of cell-surface receptors, many of which are known to be influenced by the activity of Glypicans, a family of proteoglycans that can be cleaved from the cell surface by NOTUM activity [8,10] . For example, Glypicans have been implicated in the regulation of WNT, TGFߚ, IGF, FGF, VEGF, Hh, HGF, and BMP receptor activity, primarily in studies carried out in Drosophila [8,[21][22][23][24][25][26][27][28][29][30][31][32] . In mammals, how each of the six paralogous orthologs of Drosophila Glypicans (mammalian Gpc1-6) influence activity of these receptors and in which context remains poorly understood.…”

Embryonic Development of the Kidney

“…Moreover, the medullary dysplasia observed in Gpc3-deficient mice appears to result from unrestrained proliferation and overgrowth of the ureteric bud and collecting ducts, followed by aberrant apoptosis [253,254]. The Gpc3 À/À medullary defects appear to be driven by altered responses of mutant collecting duct cells to growth factors including Fgfs [254][255][256]. Finally, mice lacking the cell cycle protein p57 KIP2 demonstrate medullary dysplasia, with fewer inner medullary collecting ducts [257].…”

The pathophysiology of paroxysmal nocturnal hemoglobinuria

“…They mediate cell adhesion and bind and modulate cytokines, thereby controlling cell growth and differentiation. Specific functions of members of the glypican family include acting as coreceptors for basic fibroblast growth factor [67], controlling cellular responses to TGF-b morphogens [68], and serving as a binding protein for tissue factor pathway inhibitor [69].…”