Alt. symbols: p72Syk

Approved name: spleen associated tyrosine kinase
Alt. names: spleen tyrosine kinase

Location: 9q22.2: 90801787 - 90898549 (+)
Gene type: protein_coding, 5 transcripts.

Scores: LoFtool: 0.007920 | pLI: 0.99854006 | LOEUF: 0.185

HGNC: 11491

NCBI: 6850, RefSeq: NG_017046.2

Ensembl: ENSG00000165025.15

LRG_ | Status: none

OMIM: 600085

Expression | ProteinAtlas

SYK encodes a non-receptor tyrosine kinase (NRTK) of the SRC subfamily that mediates signal transduction downstream of a variety of transmembrane receptors, including classical immunoreceptors like the B-cell receptor (BCR) and T-cell receptor (TCR). Initially identified as essential for BCR signaling, SYK is necessary for the maturation of B-cells (most probably at the pro-B to pre-B transition) via phosphorylation and activation of targets such as BLNK, PLCG1 and BTK. It also regulates several biological processes including innate and adaptive immune responses to fungal, bacterial and viral pathogens, cell adhesion, osteoclast maturation, platelet activation and vascular development. SYK assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T-cell receptor signaling.

Monoallelic gain-of-function (GOF) mutations in this gene have been recently associated with an immune dysregulation and systemic inflammation syndrome (PMID: 33782605). These GOF mutations included: p.S550F (found in cases with very early disease onset), p.P342T, p.M450I, and p.A353T. Truncating mutations in SYK have, on the other hand, been found in solid tumors (https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.e13519). SYK inhibitors are used to treat leukemia and lymphoma (PMID: 319 43762, 31771968, 31782972, 32005797, 33089525). Syk deletion, depletion or inhibition has been shown to reduce autoimmune or inflammatory responses in a number of mouse models of disease, including autoimmune arthritis (PMID: 22914861), chronic recurrent multifocal osteomyelitis (CRMO) (PMID: 31719149), airway fibrosis (PMID: 26308240), glomerulonephritis (PMID: 26251216), GI inflammation (PMID: 27559049, 30231985), and vasculopathy (PMID: 27102960, 29545260). On the other hand, dominant negative truncation mutants of SYK have been used in mouse studies and shown to result in impaired BCR signaling as well as impaired complement-mediated phagocytosis (PMID: 9707420, 9730884, 16449524). [Load More]