KHDRBS1
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KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''KHDRBS1''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. This gene encodes a member of the
K homology domain The K Homology (KH) domain is a protein domain that was first identified in the human heterogeneous nuclear ribonucleoprotein (hnRNP) K. An evolutionarily conserved sequence of around 70 amino acids, the KH domain is present in a wide variety o ...
-containing, RNA-binding, signal transduction-associated protein family. The encoded protein appears to have many functions and may be involved in a variety of cellular processes, including
alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
,
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
regulation, RNA 3'-end formation,
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
, and regulation of
human immunodeficiency virus The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the ...
gene expression.


Function

Sam68 (the Src-Associated substrate in Mitosis of 68 kDa) is officially called KHDRBS1 (KH domain containing, RNA binding, signal transduction associated 1). Sam68 is a KH-type RNA binding protein that recognizes U(U/A)AA direct repeats with relative high affinity. Sam68 is predominantly
nuclear Nuclear may refer to: Physics Relating to the nucleus of the atom: * Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics *Nuclear space *Nuclear ...
and its major function in the nucleus is to regulate alternative splicing by recognizing RNA sequences neighboring the included/excluded
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
(s).


Clinical significance

Sam68 influences the alternative splicing of a number of genes central to processes such as
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
and
adipogenesis Adipogenesis is the formation of adipocytes (fat cells) from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as preadipocy ...
as well as diseases such as
spinal muscular atrophy Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic ...
(SMA) and
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
.


Neurogenesis

Sam68 was demonstrated to be involved in the alternative splicing of mRNAs implicated in normal
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
using splicing-sensitive microarrays. Sam68 was also shown to participate in the epithelial-to-mesenchymal transition by regulating the alternative splicing of SF2/ASF. Sam68 was shown to regulate the activity-dependent alternative splicing of the neurexin-1 in the central nervous system with implications for neurodevelopment disorders.


Adipogenesis

Sam68 influences alternative splicing of the mTOR kinase contributing to the lean phenotype observed in the Sam68 deficient mice.


Spinal muscular atrophy

The role of Sam68 was further highlighted in spinal muscular atrophy (SMA), as Sam68 promotes the skipping of exon 7 leading to a non-functional SMN2 protein.


Cancer

Sam68 regulates the alternative splicing of a number of cancer-related genes. Direct evidence for the involvement of Sam68 in
alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
has been shown in promoting the inclusion of the variable exon 5 (v5) in
CD44 The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhes ...
correlating with cell migration potential.
CD44 The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhes ...
is a cell surface protein whose expression has been linked to cancer, with its expression predicting prognosis in a number of tumour types. In
prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
, Sam68 also interacts with splicing complex proteins
KHDRBS3 KH domain-containing, RNA-binding, signal transduction-associated protein 3 is a protein that in humans is encoded by the ''KHDRBS3'' gene. Interactions KHDRBS3 has been shown to interact with SIAH1. KHDRBS3 interacts with splicing protein Sa ...
(T-STAR) and Metadherin (MTDH) which also alter CD44 splicing. Subsequently, the knockdown of Sam68 has been shown to delay LNCaP prostate cancer cells proliferation. In addition, Sam68 in conjunction with hnRNPA1 influences the choice of the alternative 5' splice sites of Bcl-x regulating pro-survival and apoptotic pathways. The RNA binding activity of Sam68 is regulated by post-translational modifications such that Sam68 is often referred to as a STAR (Signal Transduction Activator of RNA) protein by which signals from growth factors or soluble
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, such as Src family kinases, act to regulate cellular RNA processes such as alternative splicing. For example, the Sam68-dependent CD44 alternative splicing of exon v5 is regulated by ERK
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of Sam68 and Bcl-x alternative splicing is regulated by the p59fyn-dependent phosphorylation of Sam68. Sam68 is also downstream of the
epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor recept ...
(EGFR), hepatocyte growth factor (HGF)/Met receptor (
c-Met c-Met, also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the ''MET'' gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein is ...
),
leptin Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate Energy homeostasis, energy balance by inhib ...
and
tumor necrosis factor Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
(TNF) receptors. While the role of Sam68 in these pathways is slowly emerging much remains to be determined. Sam68 has also been shown to re-localize in the cytoplasm near the plasma membrane, where it functions to transport and regulate the translation of certain mRNAs and regulates cell migration. The many roles of Sam68 in cancer have been reviewed by Bielli ''et al''.,.


Gene knockout studies

Sam68-deficient mice were generated by targeted disruption of exons 4-5 of the sam68 gene, which encode the functional region of the
KH domain The K Homology (KH) domain is a protein domain that was first identified in the human heterogeneous nuclear ribonucleoprotein (hnRNP) K. An evolutionarily conserved sequence of around 70 amino acids, the KH domain is present in a wide variety o ...
. The genotypes of the offspring from heterozygote intercrosses exhibited a Mendelian segregation at E18.5. Despite the lack of visible deformity, many of the Sam68-/- pups died at birth of unknown causes. Sam68+/- mice were phenotypically normal and Sam68-/- pups that survived the peri-natal period invariably lived to old age. Sam68-/- mice weighed less than Sam68+/+ littermates and magnetic resonance imaging analysis confirmed that young Sam68-/- mice exhibited a profound reduction in adiposity, although food intake was similar. Moreover, Sam68-/- mice were protected against dietary-induced obesity. Sam68 deficient preadipocytes (3T3-L1 cells) had impaired adipogenesis and Sam68-/- mice had ~45% less adult derived stem cells (ADSCs) in their stromal vascular fraction (SVF) from WAT.


Tumour formation ''in vivo''

Sam68-/- mice did not develop tumors and showed no immunological or other major illnesses. Sam68-/- mice did, however, have difficulty breeding due to male infertility and female subfertility. The Sam68-null mice exhibited motor coordination defects and fell from the rotating drum at lower speeds and prematurely compared to the wild-type controls. Sam68-/- mice are protected against age-induced
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
. Using the mammary tumor virus- polyoma middle T-antigen (MMTV-PyMT) mouse model of mammary tumorigenesis, it was shown that reduced Sam68 expression decreases tumor burden and
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
. Kaplan-Meier curves showed that loss of one sam68 allele (PyMT; Sam68+/-) was associated with a significant delay in the onset of palpable tumors and a significant reduction in tumor multiplicity. These findings suggest that Sam68 is required for PyMT-induced mammary tumorigenesis. The knockdown of Sam68 expression in PyMT-derived mammary cells reduced the number of lung tumor foci in athymic mice, suggesting that Sam68 is also required for mammary tumor metastasis.


References


Further reading

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