Syk

Spleen tyrosine kinase, also known as Syk, is an is_associated_with::enzyme which in humans is encoded by the SYK gene.

Function
SYK, along with is_associated_with::Zap-70, is a member of the Syk family of is_associated_with::tyrosine kinases. These non-receptor cytoplasmic tyrosine kinases share a characteristic dual is_associated_with::SH2 domain separated by a linker domain.

While Syk and Zap-70 are primarily expressed in hematopoietic tissues, there is expression of Syk in a variety of tissues. Within B and is_associated_with::T cells respectively, Syk and Zap-70 transmit signals from the B-Cell receptor and T-Cell receptor. Syk plays a similar role in transmitting signals from a variety of cell surface receptors including CD74, is_associated_with::Fc Receptor, and is_associated_with::integrins.

Function during development
Mice that lack Syk completely (Syk−/−, Syk-knockout) die during embryonic development around midgestation. They show severe defects in the development of the lymphatic system. Normally, the lymphatic system and the blood system are strictly separated from each other. However, in Syk deficient mice the lymphatics and the blood vessels form abnormal shunts, leading to leakage of blood into the lymphatic system. The reason for this phenotype was identified by a genetic fate mapping approach, showing that Syk is expressed in myeloid cells which orchestrate the proper separation of lymphatics and blood system during embryogenesis and beyond. Thus, Syk is an essential regulator of the lymphatic system development in mice.

Clinical significance
Abnormal function of Syk has been implicated in several instances of hematopoeitic malignancies including translocations involving Itk and Tel. Constitutive Syk activity can transform B cells. Several transforming viruses contain "Immunoreceptor Tyrosine Activation Motifs" (ITAMs) which lead to activation of Syk including Epstein Barr virus, is_associated_with::bovine leukemia virus, and is_associated_with::mouse mammary tumor virus.

Given the central role of SYK in transmission of activating signals within B-cells, a suppression of this tyrosine kinase might aid in the treatment of is_associated_with::autoimmune diseases. This has been demonstrated by the orally active inhibitor is_associated_with::fostamatinib (R788) in the treatment of is_associated_with::rheumatoid arthritis. The 6-month is_associated_with::double-blind, is_associated_with::placebo-controlled trial investigated clinical responses in 457 patients with is_associated_with::rheumatoid arthritis who were not sufficiently responsive to is_associated_with::methotrexate. The drug indeed caused a dose-dependent improvement in disease severity. The drug was however associated with an increase in the frequency in diarrhea, upper respiratory tract infections, is_associated_with::neutropenia. Moreover R788 increased blood pressure and a concomitant increase in treatment with antihypertensive drugs. The drug is investigational and at present the final position within the broad set of antirheumatic drugs and its long-term safety are unknown.

Syk inhibition has also been proposed as a therapy for both is_associated_with::lymphoma and is_associated_with::chronic lymphocytic leukemia. Other inhibitors of is_associated_with::B-cell receptor (BCR) signaling including is_associated_with::ibrutinib (PCI-32765) which inhibits BTK, and is_associated_with::idelalisib (PI3K inhibitor - CAL-101 / GS-1101) showed activity in the diseases as well. Newer Syk inhibitors have entered the clinic and are also in clinical development (GS-9973).

The role of Syk in epithelial malignancies is controversial. Several authors have suggested that abnormal Syk function facilitates transformation in is_associated_with::Nasopharyngeal carcinoma and is_associated_with::head and neck cancer while other authors have suggested a tumor suppressor role in breast and is_associated_with::gastric cancer.

Without Syk, the protein it makes, and genetic disruption in a panel of 55 genes thought also to be controlled by Syk, is_associated_with::breast ductal carcinoma in situ (breast DCIS, which can become invasive), it is believed that the cancer has a markedly increased tendency to invade and metastasize.

Interactions
Syk has been shown to interact with:


 * is_associated_with::Cbl gene
 * is_associated_with::CRKL,
 * is_associated_with::FCGR2A,
 * is_associated_with::FYN,
 * is_associated_with::Grb2,
 * is_associated_with::Lck,
 * is_associated_with::LYN,
 * is_associated_with::PTK2,
 * is_associated_with::PTPN6, and
 * is_associated_with::VAV1.