The diverse functions of Src family kinases in macrophages

Abstract

Macrophages are key components of the innate immune response. These cells possess a diverse repertoire of receptors that allow them to respond to a host of external stimuli including cytokines, chemokines, and pathogen-associated molecules. Signals resulting from these stimuli activate a number of macrophage functional responses such as adhesion, migration, phagocytosis, proliferation, survival, cytokine release and production of reactive oxygen and nitrogen species. The cytoplasmic tyrosine kinase Src and its family members (SFKs) have been implicated in many intracellular signaling pathways in macrophages, initiated by a diverse set of receptors ranging from integrins to Toll-like receptors. However, it has been difficult to implicate any given member of the family in any specific pathway. SFKs appear to have overlapping and complementary functions in many pathways. Perhaps the function of these enzymes is to modulate the overall intracellular signaling network in macrophages, rather than operating as exclusive signaling switches for defined pathways. In general, SFKs may function more like rheostats, influencing the amplitude of many pathways. KeywordsTyrosine kinases; signal transduction; innate immunity; integrins; Toll-like receptors; ITIM; ITAM; adhesion; migration; Hck; Fgr; Lyn; Review INTRODUCTION Src family kinases -general approachesc-Src was first described as the cellular counterpart of v-Src, the transforming gene found in Rous Sarcoma Virus, and has since been the focus of much research. Src and its other family members, referred to as Src Family Kinases (SFKs) throughout this review, have been implicated in many diverse signaling pathways in both immune (1) and non-immune cell types (2). This is apparent from the close to 25,000 PubMed hits one gets when researching these enzymes. Furthermore, a strong clinical interest has developed in SFKs based on the growing realization of their central roles in human cancer (3, 4).Src family members include c-Src, Fyn, c-Yes, Lck, Hck, c-Fgr, Lyn, Blk, and Yrk. Src, Fyn and Yes are ubiquitously expressed whereas Lck, Hck, Fgr, Lyn and Blk tend to be more restricted to cells of hematopoietic origin. Yrk has only been found in chickens. The SFKs Send correspondence to: Dr Clifford Lowell, Department of Laboratory Medicine, University of California, San Francisco, S1058, 513 Parnassus Avenue, San Francisco, CA94143-0451, Tel: 415-476-2540, Fax: 415-502-9404, clifford.lowell@ucsf.edu. HHS Public AccessAuthor manuscript Front Biosci. Author manuscript; available in PMC 2015 June 05. Published in final edited form as:Front Biosci. ; 13: 4426-4450. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript are cytoplasmic tyrosine kinases, consisting of an N-terminal unique domain, a Src homology 3 (SH3) domain that can interact with polyproline-rich motifs, a Src homology 2 (SH2) domain that binds phosphotyrosine residues, and a tyrosine kinase domain ( Figure 1A). Acylation of SFKs at their N-terminus (palmitoylation and/or myristoylation) al...

Annexin A2 Regulates Phagocytosis of Photoreceptor Outer Segments in the Mouse Retina

“…However, consistent with data obtained in ARPE19 and RPE-J cells, the ANX A2 Ϫ/Ϫ mice exhibited defective uptake of shed POS, and as mentioned above, these mice also demonstrated a marked delay in the activation of FAK and c-Src. Although c-Src has not been shown previously to be activated during POS phagocytosis, its involvement is to be expected given the close interplay of this kinase with FAK (Mitra and Schlaepfer, 2006) and the participation of both kinases in phagocytosis in other cell types (Finnemann, 2003;Abram and Lowell, 2008). FAK has been shown to lie upstream of MerTK in the hierarchy of signaling molecules that regulate POS phagocytosis in RPE cells, and our observation that FAK activation is delayed in the ANX A2 Ϫ/Ϫ mouse suggests a model in which recruitment of anx A2 to the forming phagosome leads to activation of c-Src, which in turn is required for the activation of FAK.…”

Immune Defense Protein Expression in Highly Purified Mouse Lung Epithelial Cells

“…Next, we analyzed expression of the Src family of non-receptor tyrosine kinases that act upstream of the Syk family of tyrosine kinases and have multiple roles in physiological and pathological immune signaling (23,24). Of the eight family members, Lck, Hck, Lyn, Blk, and Fgr are known to be predominantly expressed in hematopoietic cells.…”

The Src kinases Hck, Fgr, and Lyn activate Abl2/Arg to facilitate IgG-mediated phagocytosis andLeishmaniainfection

“…Src and Lyn directly bind the FcR , and macrophages lacking the SFKs Hck, Lyn and Fgr have substantial defects in IgG-mediated phagocytosis (Fitzer-Attas et al, 2000), and viral (Abram and Lowell, 2008;Bavagnoli et al, 2011;Cheng et al, 2015) and bacterial uptake (Hauck et al, 1998;Paul et al, 2008;Van Langendonck et al, 1998). SFKs phosphorylate and activate Arg (Mader et al, 2011;Plattner et al, 2004;Tanis et al, 2003), and this can be amplified by Arg autophosphorylation on a distinct regulatory site (Bradley and Koleske, 2009).…”