Cytokine-inducible SH2-containing protein is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''CISH''
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 ...
.
''CISH''
orthologs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
have been identified in most
mammals
A mammal () is a vertebrate animal of the class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three middle e ...
with sequenced genomes. CISH controls T cell receptor (TCR) signaling, and variations of ''CISH'' with certain SNPs are associated with susceptibility to bacteremia, tuberculosis and malaria.
Function
The protein encoded by this gene contains a
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, ...
and a
SOCS box domain. The protein thus belongs to the
cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family.
CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling.
The expression of this gene can be induced by IL-2, IL-3, GM-CSF and EPO in
hematopoietic
Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
cells.
Proteasome
Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
-mediated degradation of this protein has been shown to be involved in the inactivation of the
erythropoietin receptor
The erythropoietin receptor (EpoR) is a protein that in humans is encoded by the ''EPOR'' gene. EpoR is a 52 kDa peptide with a single carbohydrate chain resulting in an approximately 56–57 kDa protein found on the surface of EPO res ...
.
CISH is induced by
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. ...
(TCR) ligation and negatively regulates it by targeting the critical signaling intermediate
PLC-gamma-1 for degradation.
The deletion of Cish in effector T cells has been shown to augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. There are no changes in activity or phosphorylation of Cish's purported target,
STAT5 in either the presence or absence of Cish.
In human tumor-infiltrating lymphocytes (TIL), CISH expression has been reported to be inversely expressed with known T cell activation/exhaustion markers and regulates their expression and neoantigen reactivity. Combination therapy with checkpoint blockade synergistically results in profound tumor regressing in a pre-clinical tumor model
Interactions
CISH has been shown to
interact with
IL2RB
Interleukin-2 receptor subunit beta is a protein that in humans is encoded by the ''IL2RB'' gene. Also known as CD122; IL15RB; P70-75.
Function
The interleukin 2 receptor, which is involved in T cell-mediated immune responses, is present in 3 ...
and
Growth hormone receptor
Growth hormone receptor is a protein that in humans is encoded by the ''GHR'' gene. GHR orthologs have been identified in most mammals.
Structure
Growth hormone receptor (GHR) is a transmembrane protein consisting of 620 amino acids. The rec ...
.
and
PLCG1.
References
Further reading
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External links
* {{UCSC gene info, CISH
Genes mutated in mice