Immunobiology of the TAM receptors

Abstract

Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition

“…Receptor protein tyrosine kinase TAM family members, Tyro3, Axl and MerTK, associate with apoptotic cells by binding to PS through bridging molecules, like Gas6 or Protein S, resulting in a suppression of inflammatory responses. 15 Lack of TAM family members has been associated with autoimmune diseases, Figure 1. Binding was initiated at time ¼ 60 s and the washout (dissociation phase) was begun at t ¼ 240 s. (g) Binding of CD300b-Fc or NITR-Fc proteins to TIM1 using a two-step reaction.…”

“…2 Multiple receptors for PS exist on phagocytic cells, although not necessarily simultaneously; these include stabilins, 9,10 T cell Ig mucin (TIM) 1 and TIM4, 11,12 BAI1,13 MFGE8, which bridges PS to integrin avb3, 14 and Protein S and Gas6, which bridge PS to TAM receptors. 15 Recently, we and others demonstrated that the CD300 family members, human and mouse CD300a, 16,17 and mouse CD300f, 18,19 also bind PS, and their expression regulates apoptotic cell phagocytosis.…”

Testicular defense systems: immune privilege and innate immunity

“…77 The growth arrest-specific gene 6 (Gas6)/Protein S (ProS)-Tyro3, Axl and Mer (TAM) system is a negative regulatory immune system. 78 We showed that TAM receptor tyrosine kinases and their common ligands, Gas6 and ProS, regulate immune homeostasis in the mouse testis. TAM receptors are abundantly expressed in SCs and Leydig cells, whereas Gas6 and ProS are predominantly produced by Leydig cells.…”

HGF-induced formation of the MET–AXL–ELMO2–DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion

“…AXL was shown to act as the key regulator for the mesenchymal subtype of glioblastoma stem-like cells (13). The AXL signaling also negatively regulates the innate immune response and activation of the TAM family RTK activities promotes phagocytic clearance of apoptotic cells (14). Over-expression of AXL also confers the resistance to anti-EGFR target therapies in non-small cell lung carcinoma and in triple-negative breast cancers, and in the later case, through the EGFR mediated transactivation of AXL (15-18).…”