Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

which in humans is encoded by the ''SYK''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

Function

SYK, along with

ZAP70 ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding ...

, is a member of the Syk family of

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

s. These cytoplasmic

non-receptor tyrosine kinase A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as Adenosine triphosphate, ATP, to tyrosine residues in proteins. Non-rece ...

s share a characteristic dual

SH2 domain The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains bind to phosphorylated tyrosine residues on other proteins, ...

separated by a linker domain. However, activation of SYK relies less on phosphorylation by Src family kinases than ZAP70. SYK and ZAP70 share a common

evolutionary Evolution is the change in the heritable characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, resulting in certa ...

origin and split from a

common ancestor Common descent is a concept in evolutionary biology applicable when one species is the ancestor of two or more species later in time. According to modern evolutionary biology, all living beings could be descendants of a unique ancestor commonl ...

in the

jawed vertebrates Gnathostomata (; from Ancient Greek: (') 'jaw' + (') 'mouth') are jawed vertebrates. Gnathostome diversity comprises roughly 60,000 species, which accounts for 99% of all extant vertebrates, including all living bony fishes (both ray-finned ...

. While Syk and ZAP70 are primarily expressed in hematopoietic tissues, a variety of tissues express Syk. Within B and

T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

s, respectively, Syk and ZAP70 transmit signals from the

B-cell receptor The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 Transmembrane protein, transmemb ...

and

T-cell receptor The T-cell receptor (TCR) is a protein complex, located on the surface of T cells (also called T lymphocytes). They are responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. ...

. Syk plays a similar role in transmitting signals from a variety of cell surface receptors including

CD74 HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74 (Cluster of Differentiation 74), is a protein that in humans is encoded by the ''CD74'' gene. The invariant chain (Abbreviated Ii ...

Fc receptor In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platele ...

, and

integrin Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...

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 hematopoietic malignancies including translocations involving Itk and

Tel TEL or Tel may refer to: Businesses and organisations * Tokyo Electron, a semiconductor equipment manufacturer * TE Connectivity, a technology company, NYSE stock ticker TEL * The European Library, an Internet service Place names * Tel, Azerbaij ...

. 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 The Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the nine known Herpesviridae#Human herpesvirus types, human herpesvirus types in the Herpesviridae, herpes family, and is one of the most common viruses in ...

bovine leukemia virus Bovine leukemia virus (BLV) is a retrovirus which causes enzootic bovine leukosis in cattle. It is closely related to the human T‑lymphotropic virus type 1 ( HTLV-I). BLV may integrate into the genomic DNA of B‑lymphocytes as a DNA intermedi ...

, and

mouse mammary tumor virus Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus like the HTL viruses, HI viruses, and BLV. It belongs to the genus ''Betaretrovirus''. MMTV was formerly known as Bittner virus, and previously the "milk factor", referring to t ...

SYK inhibition

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 B cell malignancies and

autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...

s. Syk inhibition has been proposed as a therapy for both

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...

and

chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...

. Syk inhibitors are in clinical development, including cerdulatinib and entospletinib. Other inhibitors of

(BCR) signaling including

ibrutinib Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor ...

(PCI-32765) which inhibits BTK, and

idelalisib Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers. Idelalisib acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositid ...

(PI3K inhibitor - CAL-101 / GS-1101) showed activity in the diseases as well. The orally active SYK inhibitor

fostamatinib Fostamatinib, sold under the brand names Tavalisse and Tavlesse, is a tyrosine kinase inhibitor medication for the treatment of chronic immune thrombocytopenia (ITP). The drug is administered by mouth. Fostamatinib blocks the activity of the e ...

(R788) in the treatment of

immune thrombocytopenia Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is an autoimmune primary disorder of hemostasis characterized by a low platelet count in the absence of other causes. ITP often ...

. The Syk inhibitor nilvadipine has been shown to regulate amyloid-β production and

Tau Tau (; uppercase Τ, lowercase τ or \boldsymbol\tau; ) is the nineteenth letter of the Greek alphabet, representing the voiceless alveolar plosive, voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300 ...

phosphorylation and hence has been proposed as a treatment for

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

and has entered phase III clinical trials.

Epithelial malignancies

The role of Syk in epithelial malignancies is controversial. Several authors have suggested that abnormal Syk function facilitates transformation in

Nasopharyngeal carcinoma Nasopharyngeal carcinoma (NPC), or nasopharynx cancer, is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess (fossa of Rosenmüller), accounting for 50% of cases. NPC occurs ...

and

head and neck cancer Head and neck cancer is a general term encompassing multiple cancers that can develop in the head and neck region. These include cancers of the mouth, tongue, gums and lips (oral cancer), voice box ( laryngeal), throat ( nasopharyngeal, orophary ...

while other authors have suggested a tumor suppressor role in

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

and

gastric cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes ...

. Without Syk, the protein it makes, and genetic disruption in a panel of 55 genes thought also to be controlled by Syk,

ductal carcinoma in situ Ductal carcinoma ''in situ'' (DCIS), also known as intraductal carcinoma, is a pre-cancerous or non-invasive cancerous lesion of the breast. DCIS is classified as Breast cancer classification#Stage, Stage 0. It rarely produces symptoms or a ...

(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 Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

with: *

Cbl gene E3 ubiquitin-protein ligase CBL is an enzyme that is humans is encoded by the ''CBL'' (Casitas B-lineage Lymphoma) gene. ''CBL'' gene is the founding member the Cbl family. The protein CBL which is an Ubiquitin ligase, E3 ubiquitin-protein liga ...

CRKL Crk-like protein is a protein that in humans is encoded by the CRKL gene. Function v-CRK avian sarcoma virus CT10-homolog-like contains one SH2 domain and two SH3 domains. CRKL has been shown to activate the RAS and JUN kinase signaling pat ...

, *

FCGR2A Low affinity immunoglobulin gamma Fc region receptor II-a is a protein that in humans is encoded by the ''FCGR2A'' gene. Interactions FCGR2A has been shown to interact with PIK3R1 and Syk. See also * CD32 CD32 (cluster of differentiation ...

, *

FYN Proto-oncogene tyrosine-protein kinase Fyn (p59-FYN, Slk, Syn, MGC45350, Gene ID 2534) is an enzyme that in humans is encoded by the ''FYN'' gene. Fyn is a 59-kDa member of the Src family of kinases typically associated with T-cell and neurona ...

, *

Grb2 Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/ cell communication. In humans, the GRB2 protein is encoded by the ''GRB2'' gene. The protein encoded by this gene binds recepto ...

, *

Lck Tyrosin-protein kinase Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside lymphocytes and encoded in the human by the ''LCK'' gene. The Lck is a member of Src kinase family (SKF) and is important f ...

, *

LYN Lyn or LYN may refer to: People * Lyn (singer), South Korean singer * Lyn (gamer), South Korean ''Warcraft III'' player * Lyn (given name) * Lyn (surname) In science and technology * Lynx (constellation), standard abbreviation * Lyn (locomotive ...

, *

PTK2 PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the ''PTK2'' gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to ...

, *

PTPN6 Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene. Function The protein encoded by this gene is a member ...

, and *

VAV1 Proto-oncogene vav is a protein that in humans is encoded by the ''VAV1'' gene. Function The protein encoded by this proto-oncogene is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding ...

References

External links

* * {{Portal bar, Biology, border=no Tyrosine kinases