TAM Signaling in the Nervous System

Abstract

Tyro3, Axl and Mertk are members of the TAM family of tyrosine kinase receptors. TAMs are activated by two structurally homologous ligands GAS6 and PROS1. TAM receptors and ligands are widely distributed and often co-expressed in the same cells allowing diverse functions across many systems including the immune, reproductive, vascular, and the developing and adult nervous systems. This review will focus specifically on TAM signaling in the nervous system, highlighting the essential roles they play in maintaining cell survival and homeostasis, cellular functions such as phagocytosis, immunity and tissue repair. Dysfunctional TAM signaling can cause complications in development, disruptions in homeostasis which can rouse autoimmunity, neuroinflammation and neurodegeneration. The development of therapeutics modulating TAM activities in the nervous system has great prospects, however, foremost we need a complete understanding of TAM signaling pathways.

Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes

“…Our preliminary assessment also points to downregulation of PV interneuron to microglia signaling via GAS6-MERTK and upregulation of SPP1 to integrin signaling in the opposite direction in females with MDD. Together, MERTK and GAS6 promote homeostasis and neuronal survival and they are disrupted in several nervous system disorders 57 . On the other hand, microglial osteopontin (SPP1), promotes remyelination in multiple sclerosis and is neuroprotective near infarcts in stroke but in Alzheimer's disease it is part of the "disease associated microglia" signature 58 .…”

Computational Interspecies Translation Between Alzheimer’s Disease Mouse Models and Human Subjects Identifies Innate Immune Complement, TYROBP, and TAM Receptor Agonist Signatures, Distinct From Influences of Aging

“…The TAM receptor family has been reported to play a role in regulating microglial phagocytosis ( Fourgeaud et al, 2016 ; Butovsky and Weiner, 2018 ; Burstyn-Cohen and Hochberg, 2021 ; Huang et al, 2021 ). Canonical TAMR ligands such as Gas6 and Protein S bind TAM receptors through the C-terminal region and phosphatidylserine via the N-terminal region, bridging TAM expressing cells with phagocytic targets such as apoptotic bodies ( Lemke and Rothlin, 2008 ).…”

“…• TYROBP, TREM2, and complement cascade genes (C1QA, C1QB, C3) contribute to the human disease signature and are significantly increased in TASTPM heterozygous and homozygous mice Akiyama et al, 2000;Cribbs et al, 2012;Schafer et al, 2012;Zhang et al, 2013;Holtman et al, 2015;Matarin et al, 2015;Hong and Stevens, 2016;Keren-Shaul et al, 2017;Gratuze et al, 2018;Salih et al, 2019;Bartels et al, 2020 TAM family receptor agonists (Protein S and Galectin-3) associate with disease Pierce and Keating, 2014;Savage et al, 2015;Wang et al, 2015;Fourgeaud et al, 2016;Keren-Shaul et al, 2017;Krasemann et al, 2017;Mathys et al, 2017;Butovsky and Weiner, 2018;Boza-Serrano et al, 2019;Herrera-Rivero et al, 2019;Kim et al, 2019;Puigdellívol et al, 2020;Tao et al, 2020;Burstyn-Cohen and Hochberg, 2021;Huang et al, 2021 the TASTPM mouse model could be suitable as a preclinical model targeting associated microglial pathways. We suggest that TransComp-R could be useful for rational selection of mouse models in this way -the TransComp-R case study workflow we present in this study could be expanded to multiple AD mouse models.…”

The role of macrophage TAM receptor family in the acute‐to‐chronic progression of liver disease: From friend to foe?

“…Additionally, TAM receptor signalling plays an essential role in stabilizing platelets and maintaining vascular smooth‐muscle homeostasis 11 . Consistent with these diverse roles, TAM receptors are broadly expressed in a variety of tissues, including the immune, nervous, reproductive and hematopoietic systems 12 …”

“…11 Consistent with these diverse roles, TAM receptors are broadly expressed in a variety of tissues, including the immune, nervous, reproductive and hematopoietic systems. 12 TAM receptors are associated with a broad spectrum of liver diseases, such as acute injury, 13 metabolism disorders, 14 fibrosis 15 and cancer. 16 Recently, several studies suggest that TAM receptors are pivotal modulators of hepatic macrophage function.…”