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the 12th letter of the Roman alphabet (同)l

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/04/11 00:54:38」(JST)

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Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. Lck is a tyrosine kinase, which phosphorylates tyrosine residues of certain proteins involved in the intracellular signaling pathways of these lymphocytes. It is a member of the Src family of tyrosine kinases.

T cell signaling

Lck is most commonly found in T cells. It associates with the cytoplasmic tails of the CD4 and CD8 co-receptors on T helper cells and cytotoxic T cells,^[1]^[2] respectively, to assist signaling from the T cell receptor (TCR) complex. When the T cell receptor is engaged by the specific antigen presented by MHC, Lck acts to phosphorylate the intracellular chains of the CD3 and ζ-chains of the TCR complex, allowing another cytoplasmic tyrosine kinase called ZAP-70 to bind to them. Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates another molecule in the signaling cascade called LAT (short for Linker of Activated T cells), a transmembrane protein that serves as a docking site for a number of other proteins, the most important of which are Shc-Grb2-SOS, PI3K, and phospholipase C (PLC). Additionally, upon T cell activation, a fraction of kinase active Lck, translocates from outside of lipid rafts (LR) to inside lipid rafts where it interacts with and activates LR-resident Fyn, which is involved in further downstream signaling activation.^[3]^[4]

The tyrosine phosphorylation cascade initiated by Lck and Fyn culminates in the intracellular mobilization of calcium (Ca²⁺) ions and activation of important signaling cascades within the lymphocyte. These include the Ras-MEK-ERK pathway, which goes on to activate certain transcription factors such as NFAT, NF-κB, and AP-1. These transcription factors regulate the production of a plethora of gene products, most notable, cytokines such as Interleukin-2 that promote long-term proliferation and differentiation of the activated lymphocytes.

The function of Lck has been studied using several biochemical methods, including gene knockout (knock-out mice), Jurkat cells deficient in Lck (JCaM1.6), and siRNA-mediated RNA interference.

Structure

Lck is a 56-kilodalton protein. The N-terminal tail of Lck is myristoylated and palmitoylated, which tethers the protein to the plasma membrane of the cell. The protein furthermore contains a SH3 domain, a SH2 domain and in the C-terminal part the tyrosine kinase domain. The two main phosphorylation sites on Lck are tyrosines 394 and 505. The former is an autophosphorylation site and is linked to activation of the protein. The latter is phosphorylated by Csk, which inhibits Lck because the protein folds up and binds its own SH2 domain. Lck thus serves as an instructive example that protein phosphorylation may result in both activation and inhibition.

Substrates

Lck tyrosine phosphorylates a number of proteins, the most important of which are the CD3 receptor, CEACAM1, ZAP-70, SLP-76, the IL-2 receptor, Protein kinase C, ITK, PLC, SHC, RasGAP, Cbl, Vav1, and PI3K.

Inhibition

In resting T cells, Lck is constitutively inhibited by Csk phosphorylation on tyrosine 505. Lck is also inhibited by SHP-1 dephosphorylation on tyrosine 394. Lck can also be inhibited by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway.^[5]

Interactions

Lck has been shown to interact with:

ADAM15,^[6]
CD2,^[7]
CD44,^[8]^[9]
CD4,^[10]^[11]
COUP-TFII,^[12]
DLG1,^[13]
NOTCH1,^[14]
PIK3CA,^[14]^[15]
PTPN6,^[16]^[17]^[18]
PTPRC,^[19]^[20]
UNC119,^[21]
SYK,^[22]
UBE3A,^[23] and
ZAP70.^[22]^[24]

References

^ Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman SF (Jul 1988). "The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes". Proceedings of the National Academy of Sciences of the United States of America 85 (14): 5190–4. doi:10.1073/pnas.85.14.5190. PMC 281714. PMID 2455897.
^ Barber EK, Dasgupta JD, Schlossman SF, Trevillyan JM, Rudd CE (May 1989). "The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex". Proceedings of the National Academy of Sciences of the United States of America 86 (9): 3277–81. doi:10.1073/pnas.86.9.3277. PMC 287114. PMID 2470098.
^ Filipp D, Zhang J, Leung BL, Shaw A, Levin SD, Veillette A, Julius M (May 2003). "Regulation of Fyn through translocation of activated Lck into lipid rafts". The Journal of Experimental Medicine 197 (9): 1221–7. doi:10.1084/jem.20022112. PMC 2193969. PMID 12732664.
^ Filipp D, Moemeni B, Ferzoco A, Kathirkamathamby K, Zhang J, Ballek O, Davidson D, Veillette A, Julius M (Sep 2008). "Lck-dependent Fyn activation requires C terminus-dependent targeting of kinase-active Lck to lipid rafts". The Journal of Biological Chemistry 283 (39): 26409–22. doi:10.1074/jbc.M710372200. PMC 3258908. PMID 18660530.
^ Rao N, Miyake S, Reddi AL, Douillard P, Ghosh AK, Dodge IL, Zhou P, Fernandes ND, Band H (Mar 2002). "Negative regulation of Lck by Cbl ubiquitin ligase". Proceedings of the National Academy of Sciences of the United States of America 99 (6): 3794–9. doi:10.1073/pnas.062055999. PMID 11904433.
^ Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR (Feb 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". The Journal of Biological Chemistry 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. PMID 11741929.
^ Bell GM, Fargnoli J, Bolen JB, Kish L, Imboden JB (Jan 1996). "The SH3 domain of p56lck binds to proline-rich sequences in the cytoplasmic domain of CD2". The Journal of Experimental Medicine 183 (1): 169–78. doi:10.1084/jem.183.1.169. PMC 2192399. PMID 8551220.
^ Taher TE, Smit L, Griffioen AW, Schilder-Tol EJ, Borst J, Pals ST (Feb 1996). "Signaling through CD44 is mediated by tyrosine kinases. Association with p56lck in T lymphocytes". The Journal of Biological Chemistry 271 (5): 2863–7. doi:10.1074/jbc.271.5.2863. PMID 8576267.
^ Ilangumaran S, Briol A, Hoessli DC (May 1998). "CD44 selectively associates with active Src family protein tyrosine kinases Lck and Fyn in glycosphingolipid-rich plasma membrane domains of human peripheral blood lymphocytes". Blood 91 (10): 3901–8. PMID 9573028.
^ Hawash IY, Hu XE, Adal A, Cassady JM, Geahlen RL, Harrison ML (Apr 2002). "The oxygen-substituted palmitic acid analogue, 13-oxypalmitic acid, inhibits Lck localization to lipid rafts and T cell signaling". Biochimica et Biophysica Acta 1589 (2): 140–50. doi:10.1016/s0167-4889(02)00165-9. PMID 12007789.
^ Foti M, Phelouzat MA, Holm A, Rasmusson BJ, Carpentier JL (Feb 2002). "p56Lck anchors CD4 to distinct microdomains on microvilli". Proceedings of the National Academy of Sciences of the United States of America 99 (4): 2008–13. doi:10.1073/pnas.042689099. PMC 122310. PMID 11854499.
^ Marcus SL, Winrow CJ, Capone JP, Rachubinski RA (Nov 1996). "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor". The Journal of Biological Chemistry 271 (44): 27197–200. doi:10.1074/jbc.271.44.27197. PMID 8910285.
^ Hanada T, Lin L, Chandy KG, Oh SS, Chishti AH (Oct 1997). "Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes". The Journal of Biological Chemistry 272 (43): 26899–904. doi:10.1074/jbc.272.43.26899. PMID 9341123.
^ ^a ^b Sade H, Krishna S, Sarin A (Jan 2004). "The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells". The Journal of Biological Chemistry 279 (4): 2937–44. doi:10.1074/jbc.M309924200. PMID 14583609.
^ Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE (Dec 1993). "Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4-p56lck complex: the p56lck SH3 domain binds to PI 3-kinase but not PI 4-kinase". Molecular and Cellular Biology 13 (12): 7708–17. doi:10.1128/mcb.13.12.7708. PMC 364842. PMID 8246987.
^ Yu CL, Jin YJ, Burakoff SJ (Jan 2000). "Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation". The Journal of Biological Chemistry 275 (1): 599–604. doi:10.1074/jbc.275.1.599. PMID 10617656.
^ Chiang GG, Sefton BM (Jun 2001). "Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase". The Journal of Biological Chemistry 276 (25): 23173–8. doi:10.1074/jbc.M101219200. PMID 11294838.
^ Lorenz U, Ravichandran KS, Pei D, Walsh CT, Burakoff SJ, Neel BG (Mar 1994). "Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells". Molecular and Cellular Biology 14 (3): 1824–34. doi:10.1128/mcb.14.3.1824. PMC 358540. PMID 8114715.
^ Koretzky GA, Kohmetscher M, Ross S (Apr 1993). "CD45-associated kinase activity requires lck but not T cell receptor expression in the Jurkat T cell line". The Journal of Biological Chemistry 268 (12): 8958–64. PMID 8473339.
^ Ng DH, Watts JD, Aebersold R, Johnson P (Jan 1996). "Demonstration of a direct interaction between p56lck and the cytoplasmic domain of CD45 in vitro". The Journal of Biological Chemistry 271 (3): 1295–300. doi:10.1074/jbc.271.3.1295. PMID 8576115.
^ Gorska MM, Stafford SJ, Cen O, Sur S, Alam R (Feb 2004). "Unc119, a novel activator of Lck/Fyn, is essential for T cell activation". The Journal of Experimental Medicine 199 (3): 369–79. doi:10.1084/jem.20030589. PMC 2211793. PMID 14757743.
^ ^a ^b Thome M, Duplay P, Guttinger M, Acuto O (Jun 1995). "Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex". The Journal of Experimental Medicine 181 (6): 1997–2006. doi:10.1084/jem.181.6.1997. PMC 2192070. PMID 7539035.
^ Oda H, Kumar S, Howley PM (Aug 1999). "Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination". Proceedings of the National Academy of Sciences of the United States of America 96 (17): 9557–62. doi:10.1073/pnas.96.17.9557. PMC 22247. PMID 10449731.
^ Pelosi M, Di Bartolo V, Mounier V, Mège D, Pascussi JM, Dufour E, Blondel A, Acuto O (May 1999). "Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck". The Journal of Biological Chemistry 274 (20): 14229–37. doi:10.1074/jbc.274.20.14229. PMID 10318843.

External links

lck Kinase at the US National Library of Medicine Medical Subject Headings (MeSH)

Molecular and Cellular Biology portal

UpToDate Contents

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1. T細胞受容体シグナル伝達 t cell receptor signaling
2. 免疫不全症を引き起こすCD3／T細胞受容体複合体疾患 cd3 t cell receptor complex disorders causing immunodeficiency
3. ZAP-70欠損症 zap 70 deficiency
4. 前駆T細胞性急性リンパ芽球性白血病／リンパ腫の臨床症状、病理学的特徴、および診断 clinical manifestations pathologic features and diagnosis of precursor t cell acute lymphoblastic leukemia lymphoma
5. 特発性CD4陽性リンパ球減少症 idiopathic cd4 lymphocytopenia

English Journal

Integrative analysis of DNA methylation and gene expression identify a six epigenetic driver signature for predicting prognosis in hepatocellular carcinoma.

Li GX, Ding ZY, Wang YW, Liu TT, Chen WX, Wu JJ, Xu WQ, Zhu P, Zhang BX.
Journal of cellular physiology. 2019 Jul;234(7)11942-11950.
DNA methylation is a crucial regulator of gene transcription in the etiology and pathogenesis of hepatocellular carcinoma (HCC). Thus, it is reasonable to identify DNA methylation-related prognostic markers. Currently, we aimed to make an integrative epigenetic analysis of HCC to identify the effect
PMID 30536816

Identification of survival-related predictors in hepatocellular carcinoma through integrated genomic, transcriptomic, and proteomic analyses.

Dong F, Yang Q, Wu Z, Hu X, Shi D, Feng M, Li J, Zhu L, Jiang S, Bao Z.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2019 Jun;114()108856.
Patient survival time generally reflects the tumor progression and represents a key clinical parameter. In this study, we aimed to comprehensively characterize the prognosis-associated molecular alterations in hepatocellular carcinoma (HCC). In this study, copy-number changes, gene mutations, mRNA e
PMID 30981109

LCK rs10914542-G allele associates with type 1 diabetes in children via T cell hyporesponsiveness.

Zhu Q, Wang J, Zhang L, Bian W, Lin M, Xu X, Zhou X.
Pediatric research. 2019 May;().
Abnormal lymphocyte-specific protein tyrosine kinase (LCK)-related T cell hyporesponsiveness was discovered in type 1 diabetes (T1D). This study aims to investigate the potential associations between LCK single-nucleotide polymorphisms (SNPs) and the susceptibility of T1D. DNAs were extracted from b
PMID 31112992

Japanese Journal

Weighted Bott–Chern and Dolbeault cohomology for LCK-manifolds with potential

ORNEA Liviu,VERBITSKY Misha,VULETESCU Victor
東京數學物理學會記事 70(1), 409-422, 2018
… A locally conformally Kähler (LCK) manifold is a complex manifold, with a Kähler structure on its universal covering \tilde M, with the deck transform group acting on \tilde M by holomorphic homotheties. … One could think of an LCK manifold as of a complex manifold with a Kähler form taking values in a local system L, called the conformal weight bundle. …
NAID 130006334131

FBDDによる新規Type 1 1/2型ITK阻害剤の探索

直原彩枝,山本喬彦,安尾和也,服部マキ,鹿野一也
MEDCHEM NEWS 26(3), 132-137, 2016
… ATP結合サイト以外のポケットを利用する阻害剤は、一般に他キナーゼに対して高い選択性を有するが、ITKの上流で機能するlymphocyte-specific protein kinase（LCK）に対する選択性は不十分であった。 … その結果、高いキナーゼ選択性を維持しながら、LCK選択性も改善され、ヒンジ結合部位が小型化された新規リード化合物となるType 1 1/2型ITK阻害剤を得ることができた。 …
NAID 130006731097

専門スタディー3-3　T細胞　炎症性T細胞の分化を制御する低分子Gタンパク質

鈴木春巳
日本臨床免疫学会会誌 39(4), 325-325, 2016
… Rhoファミリーに属する非定型低分子GタンパクであるRhoHは，ZAP70, Syk, lckのアダプターとして機能し，TCR初期シグナル伝達に重要な働きをしていることが知られている．RhoHはαβ型T細胞の分化に重要であるが，γδ型T細胞分化への関与はよく知られていない．今回，我々は炎症性疾患に関与するIL-17産生型のγδT細胞（γδ17細胞）の分化にRhoHが必須であることを見出し，炎症応答におけるRhoHの重要性を明らかにし …
NAID 130005407748

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★リンクテーブル★

リンク元	「抗原受容体」「CD2」
拡張検索	「Lckキナーゼ」「Lck kinase」
関連記事	「L」

「抗原受容体」

LCK proto-oncogene, Src family tyrosine kinase
	The SH2 domain of human Lck colored from blue (N-terminus) to red (C-terminus).
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1BHF, 1BHH, 1CWD, 1CWE, 1FBZ, 1H92, 1IJR, 1KIK, 1LCJ, 1LCK, 1LKK, 1LKL, 1Q68, 1Q69, 1QPC, 1QPD, 1QPE, 1QPJ, 1X27, 2IIM, 2OF2, 2OF4, 2OFU, 2OFV, 2OG8, 2PL0, 2ZM1, 2ZM4, 2ZYB, 3AC1, 3AC2, 3AC3, 3AC4, 3AC5, 3AC8, 3ACJ, 3ACK, 3AD4, 3AD5, 3AD6, 3B2W, 3BRH, 3BYM, 3BYO, 3BYS, 3BYU, 3KMM, 3KXZ, 3LCK, 3MPM, 4C3F, 4D8K
Identifiers
Symbols	LCK ; IMD22; LSK; YT16; p56lck; pp58lck
External IDs	OMIM: 153390 MGI: 96756 HomoloGene: 3911 ChEMBL: 258 GeneCards: LCK Gene
EC number	2.7.10.2
Gene ontology
Molecular function	• glycoprotein binding; • antigen binding; • protein tyrosine kinase activity; • non-membrane spanning protein tyrosine kinase activity; • protein serine/threonine phosphatase activity; • protein binding; • ATP binding; • protein C-terminus binding; • protein kinase binding; • protein phosphatase binding; • protein complex binding; • SH2 domain binding; • CD4 receptor binding; • CD8 receptor binding; • identical protein binding; • phosphatidylinositol 3-kinase binding; • ATPase binding;
Cellular component	• pericentriolar material; • immunological synapse; • cytosol; • plasma membrane; • cell-cell junction; • endocytic vesicle; • extrinsic component of cytoplasmic side of plasma membrane; • membrane raft; • extracellular exosome;
Biological process	• protein phosphorylation; • cellular zinc ion homeostasis; • activation of cysteine-type endopeptidase activity involved in apoptotic process; • transmembrane receptor protein tyrosine kinase signaling pathway; • epidermal growth factor receptor signaling pathway; • aging; • blood coagulation; • fibroblast growth factor receptor signaling pathway; • response to mechanical stimulus; • response to zinc ion; • positive regulation of gene expression; • viral process; • dephosphorylation; • hemopoiesis; • platelet activation; • T cell differentiation; • T cell costimulation; • peptidyl-tyrosine autophosphorylation; • Fc-epsilon receptor signaling pathway; • regulation of cell proliferation; • response to drug; • positive regulation of tyrosine phosphorylation of Stat5 protein; • response to hydrogen peroxide; • innate immune response; • positive regulation of gamma-delta T cell differentiation; • neurotrophin TRK receptor signaling pathway; • phosphatidylinositol-mediated signaling; • regulation of defense response to virus by virus; • T cell receptor signaling pathway; • B cell receptor signaling pathway; • positive regulation of T cell receptor signaling pathway; • positive regulation of T cell activation; • leukocyte migration; • release of sequestered calcium ion into cytosol; • regulation of lymphocyte activation; • positive regulation of uterine smooth muscle contraction; • cellular response to peptide hormone stimulus; • positive regulation of intrinsic apoptotic signaling pathway;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

抗原受容体

TCR(T細胞受容体)
BCR(抗体)

シグナル伝達

	T細胞	B細胞
抗原受容体	TCR(β鎖, α鎖)	BCR(H鎖, L鎖)
受容体に付随するタンパク質	CD3δ	Igα
	CD3ε	Igβ
	CD3γ
	ζ
	CD5	CD19
	CD6	CD22
Src kinase	Lck, Fyn	Kyn, Blk, Fyn
Syc kinase ZAP-70 kinase	ZAP-70,Syk	Syk
Down stream enzymes	MAP kinase
	Vav
	PLCγ1	PLCγ1, PLCγ2
	GAP(+/-)	GAP
		PI3 kinase
Others	Ezrin
Others	Valosin-containing protein