Ligand Recognition and Homophilic Interactions in Tyro3

Abstract

The receptor Tyro3 together with Axl and Mer form the Axl/Tyro3 family of receptor tyrosine kinases. Members of this family play essential roles in spermatogenesis, immunoregulation, and phagocytosis. Gas6, the product of growth arrest-specific gene, activates the kinase activity of all three receptors. Here, we report the first biochemical and structural characterization of a member of this family, namely of a fragment spanning the two N-terminal Ig domains of the extracellular part of human Tyro3. Its ligand binding specificity profile is identical to the activation profile of the native receptor. The 1.95-Å crystal structure suggests a common ligandbinding site in this receptor family located at the interface of the Ig domains and unusually rich in cis-prolines. Furthermore, both in the crystal and in solution we observed the ligand-independent dimerization of the receptor fragment. This homophilic interaction emphasizes previous functional reports, which hinted that in addition to signal transduction, members of this family of receptors might participate in cell adhesion.

The Gas6/TAM System and Multiple Sclerosis

“…The extracellular region of the receptor consists of an immunoglobulin (Ig) domain, followed by a tandem fibronectin 3 domain; the Ig domain interacts with the SHBG-like structure of the biological ligands. The single transmembrane domain is followed by the intracellular region, which is responsible for the tyrosine kinase activity activated by receptor dimerization [9]. This is coupled to the downstream activation of different pathways, including phosphoinositide 3 kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK) 1/2, phospholipase C [10,11,12].…”

TAM receptor tyrosine kinases: Expression, disease and oncogenesis in the central nervous system

“…Signaling pathways do not operate in isolation, however: they are part of a complex network regulated by cell types, extracellular events, and microenvironments (Linger et al, 2008; Schlessinger, 2000). Sasaki et al (2006) noted that overexpression of Axl in cell lines resulted in constitutive receptor activation in the absence of Gas6, and Tyro3 has been shown to dimerize and autophosphorylate independent of ligand, a property that might be important in cell adhesion (Heiring et al, 2004; Taylor et al, 1995a). Disruption of signaling through one TAM receptor by knockdown or knockout can affect the expression and therefore the signaling of another TAM receptor (Prasad et al, 2006).…”

Macrophage–tumor crosstalk: role of TAMR tyrosine kinase receptors and of their ligands

“…Conversely, Sky overexpression promotes cancer cell survival by overcoming senescence [173]. In addition, in a similar manner to Axl, Sky can also exert adhesive functions by homophilic interaction, which potentially enhances metastasis [174].…”