TISIDB

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cell membrane Single-pass type I membrane protein Note=Membrane attachment was crucial for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway.
Domain	PF00629 MAM domain PF07714 Protein tyrosine kinase
Function	Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.

> Gene Ontology [ TOP ]
Biological Process	GO:0000187 activation of MAPK activity GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0032147 activation of protein kinase activity GO:0033674 positive regulation of kinase activity GO:0038061 NIK/NF-kappaB signaling GO:0043405 regulation of MAP kinase activity GO:0043406 positive regulation of MAP kinase activity GO:0043410 positive regulation of MAPK cascade GO:0045860 positive regulation of protein kinase activity GO:0046777 protein autophosphorylation GO:0051090 regulation of sequence-specific DNA binding transcription factor activity GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity GO:0051092 positive regulation of NF-kappaB transcription factor activity GO:0071900 regulation of protein serine/threonine kinase activity GO:0071902 positive regulation of protein serine/threonine kinase activity
Molecular Function	GO:0004674 protein serine/threonine kinase activity GO:0004702 receptor signaling protein serine/threonine kinase activity GO:0004704 NF-kappaB-inducing kinase activity GO:0004713 protein tyrosine kinase activity GO:0004714 transmembrane receptor protein tyrosine kinase activity GO:0005057 receptor signaling protein activity GO:0019199 transmembrane receptor protein kinase activity
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	-
Reactome	-

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between ALK and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between ALK and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
18469826	Lymphoma	Promote immunity	The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination.
16434370	Anaplastic Large Cell Lymphoma	Promote immunity	In vivo T-cell immune response against anaplastic lymphoma kinase in patients with anaplastic large cell lymphomas. Anaplastic lymphoma kinase (ALK) oncogenic fusion proteins, expressed in about 60% of anaplastic large cell lymphomas (ALCL), are tumor-specific molecular targets for such a malignancy. The high number of anti-ALK memory CD8 T cells present in patients' PBMC may represent a valid source of activated CTL suitable for cancer cell lysis.
27879258	Lymphoma; Lung Carcinoma; Neuroblastoma	Inhibit immunity	Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase physiologically expressed by fetal neural cells. However, aberrantly expressed ALK is involved in the pathogenesis of diverse malignancies, including distinct types of lymphoma, lung carcinoma, and neuroblastoma. NPM-ALK co-opts several intracellular signal transduction pathways, foremost being the STAT3 pathway, normally activated by cytokines from the interleukin-2 (IL-2) family to promote cell proliferation and to inhibit apoptosis. Many genes and proteins modulated by NPM-ALK are also involved in evasion of antitumor immune response. NPM-ALK uses epigenetic silencing mechanisms to downregulate tumor suppressor genes to maintain its own expression. NPM-ALK is capable of transforming primary human CD4+ T cells into immortalized cell lines indistinguishable from patient-derived ALK+ ALCL.

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of ALK in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	logFC: -1.64; FDR: 0.02150	Resistant to T cell-mediated killing
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	Total # shRNA with >= 4-fold: 1	Resistant to T-cell proliferation
24476824	shRNA	melanoma	B16	Secondary screen	Total # shRNA with >= 4-fold: 3	Resistant to T-cell proliferation

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of ALK in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.331	0.324
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.217	0.705
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.727	0.134
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.122	0.715
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.439	0.793
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.272	0.888
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.572	0.277
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.391	0.667
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.739	0.433
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.581	0.179
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.754	0.206
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.209	0.447

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of ALK in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	11.8	-11.8	0.488
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	33.3	-33.3	0.231
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	7.1	-7.1	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	14.8	6.8	8	0.247
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	14.8	8.5	6.3	0.453
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	9.5	5.9	3.6	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	12.5	0	12.5	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	7.7	9.1	-1.4	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	12.5	-12.5	0.52
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	28.6	-28.6	0.491
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	15.8	0	15.8	0.037
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	13.6	0	13.6	0.279
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	18.8	0	18.8	0.228
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of ALK. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of ALK. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by ALK. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of ALK. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of ALK expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between ALK and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	ALK
Name	anaplastic lymphoma receptor tyrosine kinase
Aliases	CD246; anaplastic lymphoma kinase (Ki-1); NBLST3; CD246 antigen; mutant anaplastic lymphoma kinase; CD antig ......
Chromosomal Location	2p23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting ALK collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting ALK.

ID	Name	Drug Type	Targets	#Targets
DB00171	ATP	Small Molecule	ABCA1, ABCB1, ABCB11, ABCC1, ABCC2, ABCC4, ABCC6, ABCC8, ABCC9, AB ......	42
DB08865	Crizotinib	Small Molecule	ALK, MET	2
DB09063	Ceritinib	Small Molecule	ALK	1
DB11363	Alectinib	Small Molecule	ALK	1
DB12267	Brigatinib	Small Molecule	ABL1, ALK, EGFR, ERBB2, ERBB4, FLT3, IGF1R, INSR, MET	9

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