Syndecan and integrin interactomes: large complexes in small spaces

Abstract

The syndecan family of transmembrane proteoglycans cooperate with integrins to regulate both early and late events in adhesion formation. The heparan sulphate chains substituted on to the syndecan ectodomains are capable of engaging ligands over great distance, while the protein core spans the plasma membrane and initiates cytoplasmic signals through a short cytoplasmic tail. These properties create a spatial paradox. The volume of the heparan sulphate chains greatly exceeds that of the integrins with which it cooperates, while the short cytodomain must bind to multiple cytoplasmic factors, despite being long enough to bind only one or two. In this review we consider the structural rearrangements that a cell undertakes to overcome spatial restrictions and compare the interactomes of syndecans and integrins to gain insight into the composition of adhesions and how they are regulated over time.

Figure 1

Literature-curated syndecan-4 interactome. Interactions are classified as direct (solid line), indirect (dotted line) or phosphorylation events (grey lines). Proteins can be classified as those identified in proteomic analyses of integrin complexes (green) and those excluded (red). Proteins involved in extracellular interactions are shown as diamonds, those that interact through a PDZ domain as squares. The complete reference list for interactions can be found in supplementary Table S1.

Figure 2

Literature-curated syndecan-1 interactome. Interactions are classified as direct (solid line), indirect (dotted line) or phosphorylation events (grey lines). Proteins can be classified as those identified in proteomic analyses of integrin complexes (green) and those excluded (red). Proteins involved in extracellular interactions are shown as diamonds, those that interact through a PDZ domain as squares. The complete reference list for interactions can be found in supplementary Table S2.

Figure 3

Spatial rearrangement of syndecan and integrin during adhesion formation. (a) Syndecan-4 detects fibronectin that is greater than 40 nm from the plasma membrane and triggers RhoG/caveolin-dependent endocytosis of integrin and Rac1-dependent polymerisation of branched actin filaments. (b) Actin polymerisation causes local membrane protrusion that causes lateral movement of syndecan-4 due to spatial constraints as the gap between membrane and matrix decreases to 10–40 nm. (c) Once the plasma membrane is within 10 nm of the ECM, integrin engages fibronectin, forming a nouveau adhesion. Integrin is recycled through an Arf6-dependent pathway. Peripheral syndecan-4 activates RhoA to cause contraction and bundling of the actin cytoskeleton.

Figure 4

Phosphorylation sites and subsequent protein interactions of the syndecan cytoplasmic domains. Serine and tyrosine residue phosphorylation by kinases and phosphatases are depicted for each syndecan, together with the consequential binding of effector proteins. Interactions are classified as direct (solid lines) and indirect (dotted lines) with those that bind via a PDZ domain shown with pink lines. Residue numbers correspond to the human sequences; asterisks indicate active protein forms. Although some of the interactions have not been empirically determined, those that have been reported are tabulated in supplementary Table S3.