Src family kinase

Last updated
Src kinase
Identifiers
SymbolSrc
CDD cd05071

Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs in invertebrates such as flies and worms, and Src homologs exist in organisms as diverse as unicellular choanoflagellates, but the SrcA and SrcB subfamilies are specific to vertebrates. Src family kinases contain six conserved domains: a N-terminal myristoylated segment, a SH2 domain, a SH3 domain, a linker region, a tyrosine kinase domain, and C-terminal tail. [1]

Contents

Src family kinases interact with many cellular cytosolic, nuclear and membrane proteins, modifying these proteins by phosphorylation of tyrosine residues. A number of substrates have been discovered for these enzymes. [2] [3] [4] Deregulation, including constitutive activation or over expression, may contribute to the progression of cellular transformation and oncogenic activity. [5]

Structure

Src family kinases contain six distinct domains including a myristoylated N-terminal segment, an SH2 domain, an SH3 domain, a linker region, a tyrosine kinase domain, and a C-terminal tail. Src kinases are known for having a characteristically short C-terminal tail that contains an autoinhibitory phosphorylation site. The SH2 and SH3 domains exist in a conformation that locks the catalytic domain into an inactive state.

Myristoylated N-terminus

Myristoylation is a post-translational modification marked by the covalent attachment of a myristoyl group to an N-terminal glycine residue. It allows for weak protein-protein and protein-lipid interactions. Myristoylation aids in the membrane association of Src kinases.

SH2 and SH3 domains

The SH2 domain of Src family kinases consist of approximately 100 amino acids. This domain acts by binding to phosphorylated tyrosine residues. The strength of binding is dependent on the amino acids surrounding the phosphorylated tyrosine. The Src kinases Fyn, Src, and Yes all bind via their SH2 domains. SH2 domains of Src family kinases play an important role in binding to growth factor receptors as well as regulating the activity of Src kinases. [6]

Linker region

The linker region of Src kinase consists of a SH2-kinase linker which intercalates between the SH3 domain and the N-terminal domain lobe. When comparing the linker regions of various members of the Src family, they were found to have little sequence similarity [7]

Tyrosine kinase domain

Tyrosine kinase domains selectively phosphorylate tyrosine residues. The tyrosine kinase domain of Src contains around 300 amino acid residues and consists of an N-terminal lobe with β-sheets and α-helices, and a C-terminal lobe that is composed primarily of α-helices. [8]

C-terminal tail

The C-terminal tail is a location of phosphorylation and dephosphorylation in Src family kinases. In c-Src, this occurs at the tyrosine residue 527. When looking at other Src molecules, most are phosphorylated at this tyrosine residue by action of the Csk family protein kinases.  

Mechanism

Activation

Src kinases are activated through a variety of ligands binding to the SH2 and SH3 domains. They can also be activated through the SH3 domain being displaced while SH2 remains engaged with the C-terminal tail. Src can be activated by receptor tyrosine kinases such as EGFR and HGF receptors. Src kinases are recruited to and activated by these receptors through the interaction of its SH2 domain with the phosphorylated tyrosine receptor. Src kinases can also be activated through displacement of their SH3 domain. When this occurs, the SH2 domains stay in contact with the C-terminal tail. An absence of regulatory proteins will also affect Src's ability to be activated properly.

Localization

Subcellular localization of Src kinases indicate their function. Src is known to associate with cell membranes, specifically the plasma membrane, the perinuclear membrane, and endosomal membranes. [9] Membrane association is partly due to the myristoyl group at the N-terminus being able to covalently attach to the membranes. Other amino acid residues at the N-terminus are important for membrane association as well because they allow Src to associate with fusion protein constructs. Myristoylation and fusion proteins work together to localize Src to cellular membranes.

Function

Src kinases transduce signals related to cellular processes such as proliferation, differentiation, motility, and adhesion. Src kinase activation leads to an increase in these processes, so Src's functionality is linked to human cancer development. [10] Inhibiting Src kinases is often a target or goal of anti-cancer drugs.

STATs and Src family kinase

Signal transducers and activators of transcription (STATs) are activated by Src family kinases in addition to growth factor receptors. STAT activation by Src family kinases often occurs downstream of growth factor receptor kinases. It has been shown that Src kinase activity is oftentimes for EGF signaling. The activation of STAT is a known requirement for tumor proliferation.

Breast cancer model

70% of breast cancer cells overexpress tyrosine kinases (specifically c-Src). A combination of c-Src and EGFR are often co-expressed in later stage tumors. This co-expression leads to a synergistic increase in mitogenesis, transformation, and tumorigenesis. Specifically, it has been found that Tyr845 in the catalytic domain of EGFR is not auto-phosphorylated. Later, it requires an association of c-Src with EGFR as well as the kinase activity of c-Src.

See also

Related Research Articles

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

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.

<span class="mw-page-title-main">Epidermal growth factor receptor</span> Transmembrane protein

The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.

<span class="mw-page-title-main">Myristoylation</span>

Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminal glycine residue. Myristic acid is a 14-carbon saturated fatty acid (14:0) with the systematic name of n-tetradecanoic acid. This modification can be added either co-translationally or post-translationally. N-myristoyltransferase (NMT) catalyzes the myristic acid addition reaction in the cytoplasm of cells. This lipidation event is the most found type of fatty acylation and is common among many organisms including animals, plants, fungi, protozoans and viruses. Myristoylation allows for weak protein–protein and protein–lipid interactions and plays an essential role in membrane targeting, protein–protein interactions and functions widely in a variety of signal transduction pathways.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

<span class="mw-page-title-main">Platelet-derived growth factor receptor</span> Protein family

Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.

<span class="mw-page-title-main">GRB2</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Adapter molecule crk</span> Protein-coding gene in the species Homo sapiens

Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.

<span class="mw-page-title-main">RET proto-oncogene</span> Mammalian protein

The RETproto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules. RET loss of function mutations are associated with the development of Hirschsprung's disease, while gain of function mutations are associated with the development of various types of human cancer, including medullary thyroid carcinoma, multiple endocrine neoplasias type 2A and 2B, pheochromocytoma and parathyroid hyperplasia.

<span class="mw-page-title-main">FYN</span> Mammalian protein found in Homo sapiens

Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.

<span class="mw-page-title-main">CBL (gene)</span> Mammalian gene

Cbl is a mammalian gene encoding the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.

<span class="mw-page-title-main">HCK</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein kinase HCK is an enzyme that in humans is encoded by the HCK gene.

<span class="mw-page-title-main">PLCG1</span> Protein-coding gene in the species Homo sapiens

Phospholipase C, gamma 1, also known as PLCG1 and PLCgamma1, is a protein that in humans involved in cell growth, migration, apoptosis, and proliferation. It is encoded by the PLCG1 gene and is part of the PLC superfamily.

<span class="mw-page-title-main">Proto-oncogene tyrosine-protein kinase Src</span> Mammalian protein found in Homo sapiens

Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src, or simply c-Src, is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. It belongs to a family of Src family kinases and is similar to the v-Src gene of Rous sarcoma virus. It includes an SH2 domain, an SH3 domain and a tyrosine kinase domain. Two transcript variants encoding the same protein have been found for this gene.

<span class="mw-page-title-main">EPH receptor B2</span> Protein-coding gene in the species Homo sapiens

Ephrin type-B receptor 2 is a protein that in humans is encoded by the EPHB2 gene.

<span class="mw-page-title-main">TEC (gene)</span> Human gene

Tyrosine-protein kinase Tec is a tyrosine kinase that in humans is encoded by the TEC gene. Tec kinase is expressed in hematopoietic, liver, and kidney cells and plays an important role in T-helper cell processes. Tec kinase is the name-giving member of the Tec kinase family, a family of non-receptor protein-tyrosine kinases.

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 ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.

Epstein–Barr virus (EBV) latent membrane protein 2 (LMP2) are two viral proteins of the Epstein–Barr virus. LMP2A/LMP2B are transmembrane proteins that act to block tyrosine kinase signaling. LMP2A is a transmembrane protein that inhibits normal B-cell signal transduction by mimicking an activated B-cell receptor (BCR). The N-terminus domain of LMP2A is tyrosine phosphorylated and associates with Src family protein tyrosine kinases (PTKs) as well as spleen tyrosine kinase (Syk). PTKs and Syk are associated with BCR signal transduction.

<span class="mw-page-title-main">Autophosphorylation</span>

Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.

Non-catalytic tyrosine-phosphorylated receptors (NTRs), also called immunoreceptors or Src-family kinase-dependent receptors, are a group of cell surface receptors expressed by leukocytes that are important for cell migration and the recognition of abnormal cells or structures and the initiation of an immune response. These transmembrane receptors are not grouped into the NTR family based on sequence homology, but because they share a conserved signalling pathway utilizing the same signalling motifs. A signaling cascade is initiated when the receptors bind their respective ligand resulting in cell activation. For that tyrosine residues in the cytoplasmic tail of the receptors have to be phosphorylated, hence the receptors are referred to as tyrosine-phosphorylated receptors. They are called non-catalytic receptors, as the receptors have no intrinsic tyrosine kinase activity and cannot phosphorylate their own tyrosine residues. Phosphorylation is mediated by additionally recruited kinases. A prominent member of this receptor family is the T-cell receptor.

References

  1. ↑ Parsons SJ, Parsons JT (October 2004). "Src family kinases, key regulators of signal transduction". Oncogene. 23 (48): 7906–9. doi:10.1038/sj.onc.1208160. PMID   15489908.
  2. ↑ Amanchy R, Zhong J, Hong R, Kim JH, Gucek M, Cole RN, et al. (December 2009). "Identification of c-Src tyrosine kinase substrates in platelet-derived growth factor receptor signaling". Molecular Oncology. 3 (5–6): 439–50. doi:10.1016/j.molonc.2009.07.001. PMC   2783305 . PMID   19632164.
  3. ↑ Amanchy R, Zhong J, Molina H, Chaerkady R, Iwahori A, Kalume DE, et al. (September 2008). "Identification of c-Src tyrosine kinase substrates using mass spectrometry and peptide microarrays". Journal of Proteome Research. 7 (9): 3900–10. doi:10.1021/pr800198w. PMC   2646669 . PMID   18698806.
  4. ↑ Luo W, Slebos RJ, Hill S, Li M, Brábek J, Amanchy R, et al. (August 2008). "Global impact of oncogenic Src on a phosphotyrosine proteome". Journal of Proteome Research. 7 (8): 3447–60. doi:10.1021/pr800187n. PMC   2579752 . PMID   18563927.
  5. ↑ Zhang S, Yu D (March 2012). "Targeting Src family kinases in anti-cancer therapies: turning promise into triumph". Trends in Pharmacological Sciences. 33 (3): 122–8. doi:10.1016/j.tips.2011.11.002. PMC   3675659 . PMID   22153719.
  6. ↑ Alonso G, Koegl M, Mazurenko N, Courtneidge SA (April 1995). "Sequence requirements for binding of Src family tyrosine kinases to activated growth factor receptors". The Journal of Biological Chemistry. 270 (17): 9840–8. doi: 10.1074/jbc.270.17.9840 . PMID   7730365.
  7. ↑ Williams JC, Wierenga RK, Saraste M (May 1998). "Insights into Src kinase functions: structural comparisons". Trends in Biochemical Sciences. 23 (5): 179–84. doi:10.1016/S0968-0004(98)01202-X. PMID   9612082.
  8. ↑ Paul MK, Mukhopadhyay AK (2004). "Tyrosine kinase - Role and significance in Cancer". International Journal of Medical Sciences. 1 (2): 101–115. doi: 10.7150/ijms.1.101 . PMC   1074718 . PMID   15912202.
  9. ↑ Bjorge JD, Jakymiw A, Fujita DJ (November 2000). "Selected glimpses into the activation and function of Src kinase". Oncogene. 19 (49): 5620–35. doi:10.1038/sj.onc.1203923. PMID   11114743.
  10. ↑ Irby RB, Yeatman TJ (November 2000). "Role of Src expression and activation in human cancer". Oncogene. 19 (49): 5636–42. doi:10.1038/sj.onc.1203912. PMID   11114744.
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