Structural basis for Gas6–Axl signalling

Sasaki, Takako; Knyazev, Pjotr; Clout, Naomi J.; Cheburkin, Yuri; Göhring, Walter; Ullrich, Axel; Timpl, Rupert; Hohenester, Erhard

doi:10.1038/sj.emboj.7600912

Cited by 258 publications

(269 citation statements)

References 41 publications

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“…The TAM receptors are most closely related to RON (also known as CD136, MST1R), the PTK receptor for macrophagestimulating protein, and to MET, the hepatocyte growth-factor receptor 1 . Similar to all other receptor PTKs, the TAMs seem to signal as dimers 7 (FIG. 1).…”

Section: Tam Receptors and Ligandsmentioning

confidence: 76%

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Immunobiology of the TAM receptors

2008

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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...

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Section: Tam Receptors and Ligandsmentioning

confidence: 76%

“…1). This SHBG-like module is both necessary and sufficient for TAM receptor binding and activation, whereas the Gla domain is dispensable for these activities 7,18 . Overall, GAS6 and protein S sharẽ 42% amino-acid identity.…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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“…, and receptor residues (37,38). Therefore, we tested if metal ions may be involved in ligand-induced TAM receptor activation.…”

Section: Resultsmentioning

confidence: 99%

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Tsou

Nguyen²,

Calarese³

et al. 2014

Journal of Biological Chemistry

191

203

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Background:The mechanisms by which ligands activate TAM receptors (TYRO3, AXL, and MER) are not well understood. Results:We created a series of TAM reporter cell lines and interrogated ligand-inducible TAM activation. Conclusion: TAMs are differentially activated by GAS6 and protein S and have distinct requirements for phosphatidylserine. Significance: Results reveal molecular mechanisms and rationale for non-overlapping functions of TAMs.

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“…The extracellular domain of Axl-Tyro3 consists of two Ig-like loops followed by two FNIII repeats and therefore has a domain organization very similar to that of Tie receptors. Recently, the crystal structure of the two Ig-like domains of the Axl-Tyro3 in complex with the natural ligand Gas6 has been determined (39). Gas6 comprises two laminin G-like domains, but interestingly in the crystal structure only the first domain binds two Axl-Tyro3 tandem Ig-like repeats at distinct and opposite sites, indicating how the receptor becomes activated through dimerization.…”

Section: The Ecd Of Tie Receptors Contains a Third Ig-like Domain-mentioning

confidence: 99%

Structure of the Extracellular Domain of Tie Receptor Tyrosine Kinases and Localization of the Angiopoietin-binding Epitope

Macdonald

Progias

Ciani

et al. 2006

Journal of Biological Chemistry

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Angiogenesis is essential for tissue repair and regeneration during wound healing but also plays important roles in many pathological processes including tumor growth and metastasis. The receptor protein tyrosine kinase Tie2 and its ligands, the angiopoietins, have important functions in the regulation of angiogenesis. Here, we report a detailed structural and functional characterization of the extracellular region of Tie2. Sequence analysis of the extracellular domain revealed an additional immunoglobulin-like domain resulting in a tandem repeat of immunoglobulin-like domains at the N terminus of the protein. The same domain organization was also found for the Tie1 receptor that shares a high degree of homology with Tie2. Based on structural similarities to other receptor tyrosine kinases and cell adhesion molecules, we demonstrate that the N-terminal two immunoglobulin-like domains of Tie2 harbor the angiopoietin-binding site. Using transmission electron microscopy we furthermore show that the extracellular domain of Tie receptors consists of a globular head domain and a short rod-like stalk that probably forms a spacer between the cell surface and the angiopoietin-binding site. Mutational analysis demonstrated that the head domain consists of the three immunoglobulin-like domains and the three epidermal growth factorlike modules and that the stalk is formed by the three fibronectin type III repeats. These findings might be of particular interest for drug development because Tie receptors are potential targets for treatment of angiogenesis-associated diseases.Proper regulation of angiogenesis is required for the normal growth of embryonic and postnatal tissues as well as physiological processes in the adult such as the continuous remodeling of the female reproductive system and wound healing (1, 2). In contrast, dysregulation of angiogenesis contributes to numerous malignant, ischemic, inflammatory, infectious, and immune disorders including conditions such as diabetic retinopathy and tumor growth and metastasis (1, 2). The angiopoietin (Ang) 3 /Tie signaling system plays important roles in the regulation of angiogenesis (3, 4). Tie1 and Tie2 constitute a family of vascular-specific receptor tyrosine kinases (RTKs) that are expressed mainly on endothelial cells but also in certain hematopoietic cells (5-7). Angiopoietins are a family of four distinct growth factor ligands that bind to Tie2 but not Tie1 (8 -10). They are unique and differ from other growth factors by having opposing effects on receptor phosphorylation. Overexpression and knock-out studies in mice have revealed that Ang1 is an agonist promoting stabilization of vessels by maximizing interactions between endothelial cells and their surrounding support cells and the extracellular matrix (11, 12). In contrast Ang2 was found to be a context-dependent antagonist that promotes angiogenic sprouting or vessel regression depending on the expression of vascular endothelial growth factor-A (13, 14). Ang3 and Ang4 also show context-dependent actions as anta...

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Structural basis for Gas6–Axl signalling

Cited by 258 publications

References 41 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Structure of the Extracellular Domain of Tie Receptor Tyrosine Kinases and Localization of the Angiopoietin-binding Epitope

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