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 [5] [6] and is part of the PLC superfamily.
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 [5] [6] and is part of the PLC superfamily.
PLCγ1 is a cell growth factor [7] [8] from the PLC superfamily. PLCγ1 is used during cell growth [7] and in cell migration [9] and apoptosis, [8] all of which are vital cell processes that, if disrupted by mutations, can cause cancerous cells to form within the body. Mutations in this protein show an increase in issues in cells regarding regulation of proliferation and their cell signaling. [7] PLCγ1 roles are also involved in neuronal actin growth, calcium signaling, and brain development. [10] [8] [9] It is highly regulated by multiple factors, such as PIK3, AMPK, and FAK. [8] [11] It is part of the PIP3 pathway and leads to and increase in calcium in the cells. In neuronal cells, PLCγ1 is highly involved in actin cytoskeleton organization and synaptic plasticity. [10] The basic PLCγ1 pathway, as scientists currently understand it, is seen below.
The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of receptor-mediated tyrosine kinase activators. For example, when activated by SRC, the encoded protein causes the Ras guanine nucleotide exchange factor RASGRP1 to translocate to the Golgi apparatus, where it activates Ras. Also, this protein has been shown to be a major substrate for heparin-binding growth factor 1 (acidic fibroblast growth factor)-activated tyrosine kinase. The receptor protein tyrosine phosphatase PTPmu (PTPRM) is capable of dephosphorylating PLCG1. [12] Two transcript variants encoding different isoforms have been found for this gene. [13]
Common to all PLC isozymes, PLCG1 consists of an N-terminal PH domain, which translocates PLC to the plasma membrane and binds PIP3; [14] four EF hands; an X and Y catalytic region comprising the TIM barrel; and a C-terminal C2 domain. [15] Specific to the PLCG isozymes is a large separation between the X and Y domains consisting of a split PH domain, tandem SH2 domains, and an SH3 domain. [15] The SH2 domains bind phosphorylated tyrosine residues on target proteins via their FLVR sequence motifs, activating the catalytic function of PLCg; and the SH3 domain binds to proline-rich sequences on the target protein. [15]
PLCG1 can be activated by receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases. For example, when activated, fibroblast growth factor receptor 1 and epidermal growth factor receptor are RTKs that have phosphorylated tyrosines, which provide docking sites for PLCG1 SH2 domains. [15] The activated RTKs phosphoylate PLCG1 at tyrosines located at position 472, 771, 775, 783, and 1254. [16] Non-receptor tyrosine kinases interact with PLCG1 in large complexes at the plasma membrane. For example, in T cells, Lck and Fyn (Src family kinases) phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) on the T-cell antigen receptor (TCR). [15] The phosphorylated ITAMs recruit ZAP-70, which phosphorylates tyrosines in LAT and SLP-76. PLCg1 binds to LAT through its n-terminal SH2 domain and to SLP-76 via its SH3 domain. [15]
Has been shown to interact with CISH which negatively regulates it by targeting it for degradation. [17] 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 vitro studies have shown signs of PLCγ1 having many cell-motility functions, however in vivo have not been able to show a physiological role for PLCγ1. [18] While PLCγ1 is well documented and easily found in the body, clear connections and roles for PLCγ1 have been difficult to find in in vivo studies. Despite this, there is still able to find links between levels of PLCγ1 and cancer patient survivability.
Mutations in PLCγ1 can lead to cancer cell proliferations and inhibition can lead to tumor growth. [19] PLCγ1 is involved in cell proliferation, and mutations cause it to be over expressed and help the progression of tumor cells. This aspect of PLCγ1 also helps cancer migration and metastasis away from the original tumor cells. [20] [21] There is also a link between PLCγ1 and PDK, the PDK-PLCγ1 pathway, which is a vital part of cancer cell invasion. [21]
The inhibition of PLCγ1 is linked to a decrease in tumor growth and metastasis. [19] [20] PLCγ1 is acting as a vital part in stopping apoptosis in cells, and thus by inhibiting PLCγ1 the body better allows programmed cell death and avoidance of tumors. [19] [20] The main role found for PLCγ1 is cell growth, and this role in specific is why it is becoming more commonly studied for anti-cancer drugs. [20] [21] Tissue samples from cancer patients the PLCγ1 levels are not elevated, however, regulatory factors for this proteins are lowered and that amplification of PLCγ1 is extremely high. [20] The regulatory proteins that stop PLCγ1 have been turned off by the cell, which means that while there is no increase in the physical protein PLCγ1 there is an increase in how much work it is doing - nothing is stopping it from over working itself. Studies also showed that adding new regulatory to cells in vitro helped reduce previously amplified PLCγ1. [19] This information has encouraged PLCγ1 becoming an anti-cancer drug target despite the issues that come with targeting intermembrane proteins. [19] [21] [22]
PLCG1 has been shown to interact with:
Tyrosin-protein kinase Lck 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 (SFK) and is important for the activation of T-cell receptor (TCR) signaling in both naive T cells and effector T cells. The role of Lck is less prominent in the activation or in the maintenance of memory CD8 T cells in comparison to CD4 T cells. In addition, the constitutive activity of the mouse Lck homolog varies among memory T cell subsets. It seems that in mice, in the effector memory T cell (TEM) population, more than 50% of Lck is present in a constitutively active conformation, whereas less than 20% of Lck is present as active form in central memory T cells. These differences are due to differential regulation by SH2 domain–containing phosphatase-1 (Shp-1) and C-terminal Src kinase.
Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.
Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). The standard pronunciation for this protein is "track bee".
Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.
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.
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.
Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene.
Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.
Lymphocyte cytosolic protein 2, also known as LCP2 or SLP-76, is a signal-transducing adaptor protein expressed in T cells and myeloid cells and is important in the signaling of T-cell receptors (TCRs). As an adaptor protein, SLP-76 does not have catalytic functions, primarily binding other signaling proteins to form larger signaling complexes. It is a key component of the signaling pathways of receptors with immunoreceptor tyrosine-based activation motifs (ITAMs) such as T-cell receptors, its precursors, and receptors for the Fc regions of certain antibodies. SLP-76 is expressed in T-cells and related lymphocytes like natural killer cells.
The Linker for activation of T cells, also known as linker of activated T cells or LAT, is a protein involved in the T-cell antigen receptor signal transduction pathway which in humans is encoded by the LAT gene. Alternative splicing results in multiple transcript variants encoding different isoforms.
Tyrosine-protein kinase Lyn is a protein that in humans is encoded by the LYN gene.
Cbl is a mammalian gene family. CBL gene, a part of the Cbl family, encodes 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.
Tyrosine-protein kinase HCK is an enzyme that in humans is encoded by the HCK gene.
GRB2-associated-binding protein 1 is a protein that in humans is encoded by the GAB1 gene.
Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 is an enzyme that in humans is encoded by the PLCG2 gene.
Cytoplasmic protein NCK2 is a protein that in humans is encoded by the NCK2 gene.
BAG family molecular chaperone regulator 3 is a protein that in humans is encoded by the BAG3 gene. BAG3 is involved in chaperone-assisted selective autophagy.
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.
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.
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