Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation

Abstract

SummarySyndecan-1 (Sdc1) engages and activates the avb3 (and/or avb5) integrin when clustered in human carcinoma and endothelial cells. Although the engagement is extracellular, the activation mechanism is cytoplasmic. This talin-dependent, inside-out signaling pathway is activated downstream of the insulin-like growth factor-1 receptor (IGF1R), whose kinase activity is triggered by Sdc1 clustering. In vitro binding assays using purified receptors suggest that association of the Sdc1 ectodomain with the integrin provides a 'docking face' for IGF1R. IGF1R docking and activation of the associated integrin is blocked by synstatin (SSTN 92-119 ), a peptide derived from the integrin engagement site in Sdc1. IGF1R colocalizes with avb3 integrin and Sdc1 in focal contacts, but fails to associate with or activate the integrin in cells either lacking Sdc1 or expressing Sdc1 D67-121 , a mutant that is unable to form the Sdc1-integrin-IGF1R ternary complex. Integrin activation is also blocked by IGF1R inhibitors or by silencing IGF1R or talin expression with smallinterfering RNAs (siRNAs). In both cases, expression of the constitutively active talin F23 head domain rescues integrin activation.We recently reported that SSTN 92-119 blocks angiogenesis and impairs tumor growth in mice, therefore this Sdc1-mediated integrin regulatory mechanism might be a crucial regulator of disease processes known to rely on these integrins, including tumor cell metastasis and tumor-induced angiogenesis.

Syndecan-1 and Its Expanding List of Contacts

“…While integrins have been shown to associate with SYNDECAN-1 AND WOUND HEALING numerous kinases, including FAK and epidermal growth factor receptor (EGFR), thus far, sdc1 has only been shown to associate directly with the insulin-like growth factor 1 receptor (IGF1R); along with a v -containing integrin heterodimers, sdc1 and IGF1R form a ternary complex that induces cell signaling. 46 Association between sdc2 and integrin is more complex. A juxtamembrane sequence on the C1 domain of sdc2 associates with the integral membrane tyrosine phosphatase, CD148, which in turn associates with b 1 -family integrins.…”

“…This lead to the characterization of synstatin, a sdc1-derived peptide that binds to integrins and reduces cancer cell invasion and tumor angiogenesis. 45,46,55 Sdc1-mediated activation of integrins impacts wound healing. Corneal wound healing studies performed using sdc1-null mice show delayed reepithelialization not caused by altered cell proliferation.…”

“…However, the increased integrin surface expression on sdc1-null keratinocytes also suggests the possibility that reduced trafficking of integrins and other receptors from the cell surface may also play important roles. 43 The mechanism leading altered integrin activation in mice lacking sdc1 was explained through critical experiments performed by Beauvais et al 55 These 45,46 Sdc1-null mice and sdc1-depleted cells are widely used to study the mechanism underlying many different types of injuries. The description of phenotypes seen in over 30 studies is presented in a recent review by Teng et al 4 Collectively, these studies show that sdc1 aids in wound healing by enhancing cell migration, controls viral attachment and entry, regulates microbial defense, generates chemokine gradients, and modifies cell signaling.…”

Syndecan as a Messenger to Link Diabetes and Cancer

“…Recently, it has been found that syndecan-1 interacts with IGF-1 receptor to activate integrin (Beauvais and Rapraeger, 2010). It is reasonable to speculate insulin on cancer cell proliferation in vivo may involve an indirect mechanism, such as IGF-1 stimulation.…”

“…Thus the syndecans involve in synchronized expression patterns during embryogenesis and malignant transformation. These cell-cell interactions via their extracellular matrix ligands control cell proliferation, dynamic cytoskeletal remodeling, apoptosis and gene expression.Over the last few years, it has been widely accepted that heparan sulfate proteoglycans play a role in growth control, cell spreading, cellular recognition, cellular adhesion, and signaling, possibly as co -receptors with integrins, IGF-1R and cell -cell adhesion molecules, including fi bronectin, vitronectin, laminins, and the fi brillar collagens (Bernfi eld et al, 1999;Woods, 2001;Alexopoulou et al, 2007;Beauvais and Rapraeger, 2010). In addition, all syndecans have dibasic peptide sequence adjacent to the plasma membrane.…”