GAS6 Mediates Adhesion of Cells Expressing the Receptor Tyrosine Kinase Axl

Abstract

Axl is a receptor tyrosine kinase that contains both immunoglobulin and fibronectin III repeats in its extracellular domain reminiscent of cell adhesion molecules. Expression of the receptor tyrosine kinase Axl in the 32D myeloid cell line permits aggregation of cells in response to treatment with the native ligand GAS6; this aggregation was not observed in untreated 32D-Axl cells nor in treated parental cells. This aggregation can be blocked by the addition of excess Axl extracellular domain peptide and does not require intracellular Axl kinase activity. Cell surface binding activity of GAS6 was mapped to distinct plasma membrane interacting domains that are separate from the GAS6 motifs that engage the Axl receptor. This suggests that aggregation is mediated by a heterotypic intercellular mechanism whereby cell-bound GAS6 interacts with Axl receptor on an adjacent cell. This mechanism is supported by our observation that GAS6 binds to 32D parental cells which then permits their aggregation with untreated 32D-Axl cells. We have recently demonstrated that the GAS6-Axl interaction does not initiate mitogenesis in 32D cells. When considered with the adhesion results, these data suggest that an important biological function of the Axl-GAS6 interaction is to mediate cell-cell binding.

Ligand Recognition and Homophilic Interactions in Tyro3

“…Because the members of the Axl/Tyro3 family are expressed in a great variety of tissues, it is not unlikely that differently glycosylated forms of these receptors exist. Glycosylation-dependent dimerization would explain the observation that in the case of Axl, overexpression causes cell aggregation in some cell types as well as aggregation of Axl-coated polymer beads through homophilic binding (29); although in other cell lines such a homophilic mechanism could not be confirmed (19). Unfortunately, until now, experimental data regarding the tissuespecific glycosylation of the Axl/Tyro3 receptor family is not available.…”

“…Gas6, a vitamin K-dependent protein encoded by growth arrest-specific gene 6 (17), binds to Axl, Tyro3, and Mer with nanomolar affinities (0.4, 2.9, and 29 nM, respectively) (18). The interaction between Axl and Gas6 has been implicated in cell adhesion processes (19,20), prevention of apoptosis (21), and cell proliferation (22), whereas Tyro3-Gas6 signaling was reported to stimulate osteoclastic bone resorption (23). In fibroblasts, high expression of Tyro3 or Axl has been found to cause transformation even in the absence of the ligand (9,24).…”

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

“…Overexpression of Axl can transform fibroblasts even in the absence of a ligand (Burchert et al, 1998). Axl is known to induce cell survival (Melaragno et al, 2004;van Ginkel et al, 2004), proliferation (Stenhoff et al, 2004;Sainaghi et al, 2005), stimulation of cell migration and cell-cell adhesion (McCloskey et al, 1997). Moreover, an increased expression of Axl is associated with invasion, metastasis, angiogenesis, and is found in metastatic colon, prostate carcinoma, gastric and endometrial cancers, breast cancers, lung cancers and sarcomas (Hafizi and Dahlback, 2006).…”

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

“…Gas6 binds to TAM family members with different affinities. Gas6 was first discovered as an upregulated gene in growth-arrested cells (12), and further studies with Gas6 signaling suggested its role in cell survival (13,14), proliferation (15,16), stimulation of cell migration (17), and cell-cell adhesion through Axl (18). Intracellular signaling of Axl is also activated by its homophilic and heterophilic interactions (19), mediated mainly by a multisubstrate docking site (20).…”