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CRK (v-crk sarcoma virus CT10 oncogene homolog (avian))

Written2012-03Shinya Tanaka
Laboratory of Cancer Research, Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

(Note : for Links provided by Atlas : click)

Identity

Other aliasCRKII
p38
LocusID (NCBI) 1398
Atlas_Id 40149
Location 17p13.3  [Link to chromosome band 17p13]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ABR (17p13.3) / CRK (17p13.3)CDS2 (20p12.3) / CRK (17p13.3)CRK (17p13.3) / CRK (17p13.3)
CRK (17p13.3) / WDR47 (1p13.3)CYP19A1 (15q21.2) / CRK (17p13.3)FABP6 (5q33.3) / CRK (17p13.3)
FAM20B (1q25.2) / CRK (17p13.3)LHFPL2 (5q14.1) / CRK (17p13.3)MYO1C (17p13.3) / CRK (17p13.3)
PLA2R1 (2q24.2) / CRK (17p13.3)TAF8 (6p21.1) / CRK (17p13.3)TUSC5 (17p13.3) / CRK (17p13.3)
WDR6 (3p21.31) / CRK (17p13.3)YWHAE (17p13.3) / CRK (17p13.3)
Note CT10 regulator of kinase.

DNA/RNA

Note Crk belongs to an adaptor family of protein mostly composed of SH2 (src homology 2) and SH3 domains.
 
  Crk-II gene comprises of three exons spanning on chromosome 17p13.3.
Description The human genomic DNA sequence contains 3 exons.
Transcription The length of open reading frame of transcript is 912 mer and translated to a 304 residues protein referred as c-Crk-II. By alternative splicing, 610-778 were deleted and truncated protein encoding 203 amino acids protein as c-Crk-I was generated. Recently, Crk-III which comprises 283 amino acids was reported.
Pseudogene Not identified.

Protein

Note Crk was originally isolated as avian retrovirus (CT10, chicken tumor No. 10) encoding oncoprotein as v-Crk (viral Crk, CT10 regulator of kinase).
Crk-II is composed of SH2-SH3(N)-SH3(C) and alternative splicing product Crk-I which deleted SH3(C) as SH2-SH3(N).
 
  Tyrosine Y221 (human) of CrkII can be tyrosine phosphorylated and SH2 domain of CrkII binds to pY221 intramolecularly.
Description NMR analysis of Crk-I, Crk-II, and phosphorylated form of Crk-II (aa 1-231). Crk-I has flexible structure of the linker region, thus individual SH2 or SH3 domain freely access to the targets (data not shown). Unphosphorylated form of Crk-II exhibits compact structure, and each SH domains were relatively fixed around inter SH3 region (designated as ISC: inter SH3 core; yellow in the figure below). In this form, interaction surface of SH3(N) is in the semi-closed status. Upon tyrosine phosphorylation of Y221, SH2 binds to pY221 and structure is dramatically altered and SH3(N) surface is completely blocked by internal structure. Thus, pCrk-II is signaling-OFF form.
 
  Structure of signaling adaptor protein CrkII. Adapted from Kobashigawa et al. (2007).
Expression Ubiquitous.
Localisation Mostly cytoplasm.
Function Signaling adaptor protein which links tyrosine kinases and small G proteins.
Crk transmits signals from extracellular stimuli such as growth factors and extracellular matrices. SH2 domain of Crk bound to tyrosine phosphorylated peptide motif as YXXP. In focal adhesion complex, Crk binds to p130Cas which possesses six Crk binding consensus sequences and to paxillin. Crk activates Fak and transmit signals to PI3 kinase. Crk also binds to growth factor receptors such as EGFR or FGF, in addition to downstream signaling scaffold protein Gab1 which is mainly activated by HGF. CRK transmits signals to small G proteins through its SH3 domain binding target C3G and DOCK180 those can activate Rap/R-Ras and Rac, respectively, and regulates cell growth, adhesion, and motility.
Crk plays various roles including cell growth, differentiation, phagocytosis, glucose transport, and infectious diseases.
Homology CrkL (Crk-like).

Implicated in

Note
  
Entity Various diseases
Note Crk is overexpressed in various human cancers especially in lung adenocarcinoma and in brain tumor. Crk knockdown study demonstrates the essential roles for Crk in malignant potentials of various human cancers including ovarian cancer, sarcoma, and brain tumor. Recently, microRNA-126 was shown to suppress lung cancer growth by the suppression of Crk expression. Crk has been reported to bind to NS1 protein of influenza virus type H5N1, CagA protein of Helicobacter pylori, and also known to regulate the infection of Pseudomonas aeruginosa and Shigella flexneri. Therefore, Crk can be a therapeutic target molecule for cancer and infectious diseases.
  
  
Entity Lung cancer
Note 96 cases of lung adenocarcinoma were analyzed by using Gene chip and in the cases of stage III, mRNA levels of Crk were increased comparing to those of in stage I (Beer et al., 2002).
Affymetrix oligonucleotide arrays were used to analyze 86 lung adenocarcinomas and 10 uninvolved lung tissues, and Crk mRNA expression was increased in more advanced (stage III versus stage I), larger (T2-4 versus T1), and poorly differentiated tumors and in tumors from patients demonstrating poor survival (Miller et al., 2003).
Immunohistochemical analysis of Crk-II demonstrated that the levels of Crk-II were significantly elevated in most of the tumors, particularly in the colon and lung cancers. Furthermore, immunoblot analysis using human lung cancer cell lines revealed that the expression levels of Crk-II were correlated to growth rates of cells (Nishihara et al., 2002).
Prognosis Expression of Crk mRNA was increased in patients with poor prognosis (P=0.00034) (Miller et al., 2003).
  
  
Entity Brain tumor
Note CrkII mRNA was detected both in normal brain and glioblastoma tissues, whereas crkI mRNA levels were quite low in normal brain and up-regulated in glioblastoma tissues. Expression of CrkI but not CrkII in glioblastoma U87MG cells induced transformation that stimulated cell migration and invasion concomitant with tyrosine phosphorylation of p130 Cas (Takino et al., 2003).
Crk-knockdown cell lines of glioblastoma KMG4 was established by siRNA, and early phase of cell adhesion to laminin was found to be suppressed. Wound healing assay revealed the decreased cell motility in Crk knockdown cells, and suppression of both anchorage-dependent and -independent growth were demonstrated in these cells. Furthermore, in vivo tumor forming potential was also markedly suppressed (Wang et al., 2007).
  
  
Entity Ovarian cancer
Note Crk expression was targeted in the human ovarian cancer cell line MCAS through RNA interference, resulting in disorganized actin fibers, reduced number of focal adhesions, and decreased Rac activity in association with suppression of cell motility and invasion, and anchorage-dependent growth in soft agar. Tumor forming potential in nude mice was attenuated and intraperitoneal dissemination was not observed when Crk knockdown cells were injected into the peritoneal cavity (Linghu et al., 2006).
  
  
Entity Breast cancer
Note CrkI/II knockdown resulted in a significant decrease in migration and invasion of multiple malignant breast and other human cancer cell lines (MDA-231, MDA-435s, H1299, KB, and HeLa). Moreover, CrkI/II knockdown decreased cell spreading on extracellular matrix and led to a decrease in actin stress fibers and the formation of mature focal adhesions. Using immunohistochemistry, we show elevated CrkI/II protein levels in patients with breast adenocarcinoma (Rodrigues et al., 2005).
  
  
Entity Synovial sarcoma
Note Crk adaptor protein is required for the sustained phosphorylation of Gab1 in response to HGF, leading to the enhanced cell motility of human synovial sarcoma cell lines SYO-1, HS-SY-II, and Fuji. Crk knockdown by RNA interference disturbed this HGF-induced tyrosine phosphorylation of Gab1. The elimination of Crk in these cells induced the disorganization of actin cytoskeleton and complete abolishment of HGF-mediated Rac1 activation and cell motility. Furthermore, the depletion of Crk remarkably inhibited the tumor formation and its invasive growth in vivo (Watanabe et al., 2006).
  
  
Entity Oral cancer
Note The expression of CRKII in 71 primary oral squamous cell carcinomas and 10 normal oral mucosal specimens was determined immunohistochemically, and the correlation of CRKII overexpression with clinicopathological factors was evaluated. Overexpression of CRKII was detected in 41 of 70 oral squamous cell carcinomas, the frequency being more significant than in normal oral mucosa. In addition, CRKII overexpression was more frequent in higher-grade cancers according to the T classification, N classification, and invasive pattern. Moreover, RNAi-mediated suppression of CRKII expression reduced the migration and invasion potential of an oral squamous cell carcinoma cell line, OSC20 (Yamada et al., 2011).
  
  
Entity Endometriosis
Note The expression levels of miR-126 and and its putative target Crk mRNA were quantified using real time PCR in ectopic endometrium and eutopic endometrium in patients with endometriosis. The expression level of miR-126 was significantly downregulated in ectopic endometrium whereas the protein levels of Crk was increased. Thus, miR-126 may play an initial role in the development and progression of endometriosis (Liu et al., 2012).
  

Bibliography

Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling.
Heikkinen LS, Kazlauskas A, Melen K, Wagner R, Ziegler T, Julkunen I, Saksela K.
J Biol Chem. 2008 Feb 29;283(9):5719-27. Epub 2007 Dec 28.
PMID 18165234
 
v-Crk activates the phosphoinositide 3-kinase/AKT pathway in transformation.
Akagi T, Shishido T, Murata K, Hanafusa H.
Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7290-5.
PMID 10852971
 
Gene-expression profiles predict survival of patients with lung adenocarcinoma.
Beer DG, Kardia SL, Huang CC, Giordano TJ, Levin AM, Misek DE, Lin L, Chen G, Gharib TG, Thomas DG, Lizyness ML, Kuick R, Hayasaka S, Taylor JM, Iannettoni MD, Orringer MB, Hanash S.
Nat Med. 2002 Aug;8(8):816-24. Epub 2002 Jul 15.
PMID 12118244
 
c-Abl kinase regulates the protein binding activity of c-Crk.
Feller SM, Knudsen B, Hanafusa H.
EMBO J. 1994 May 15;13(10):2341-51.
PMID 8194526
 
Crk family adaptors-signalling complex formation and biological roles.
Feller SM.
Oncogene. 2001 Oct 1;20(44):6348-71. (REVIEW)
PMID 11607838
 
Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling.
Heikkinen LS, Kazlauskas A, Melen K, Wagner R, Ziegler T, Julkunen I, Saksela K.
J Biol Chem. 2008 Feb 29;283(9):5719-27. Epub 2007 Dec 28.
PMID 18165234
 
CrkII regulates focal adhesion kinase activation by making a complex with Crk-associated substrate, p130Cas.
Iwahara T, Akagi T, Fujitsuka Y, Hanafusa H.
Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17693-8. Epub 2004 Dec 14.
PMID 15598735
 
Activation of Rac1 by a Crk SH3-binding protein, DOCK180.
Kiyokawa E, Hashimoto Y, Kobayashi S, Sugimura H, Kurata T, Matsuda M.
Genes Dev. 1998 Nov 1;12(21):3331-6.
PMID 9808620
 
Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK.
Kobashigawa Y, Sakai M, Naito M, Yokochi M, Kumeta H, Makino Y, Ogura K, Tanaka S, Inagaki F.
Nat Struct Mol Biol. 2007 Jun;14(6):503-10. Epub 2007 May 21.
PMID 17515907
 
Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS.
Linghu H, Tsuda M, Makino Y, Sakai M, Watanabe T, Ichihara S, Sawa H, Nagashima K, Mochizuki N, Tanaka S.
Oncogene. 2006 Jun 15;25(25):3547-56. Epub 2006 Feb 20.
PMID 16491127
 
Expression of miR-126 and Crk in endometriosis: miR-126 may affect the progression of endometriosis by regulating Crk expression.
Liu S, Gao S, Wang XY, Wang DB.
Arch Gynecol Obstet. 2012 Apr;285(4):1065-72. Epub 2011 Oct 20.
PMID 22012249
 
Elmo1 inhibits ubiquitylation of Dock180.
Makino Y, Tsuda M, Ichihara S, Watanabe T, Sakai M, Sawa H, Nagashima K, Hatakeyama S, Tanaka S.
J Cell Sci. 2006 Mar 1;119(Pt 5):923-32.
PMID 16495483
 
Two species of human CRK cDNA encode proteins with distinct biological activities.
Matsuda M, Tanaka S, Nagata S, Kojima A, Kurata T, Shibuya M.
Mol Cell Biol. 1992 Aug;12(8):3482-9.
PMID 1630456
 
A novel viral oncogene with structural similarity to phospholipase C.
Mayer BJ, Hamaguchi M, Hanafusa H.
Nature. 1988 Mar 17;332(6161):272-5.
PMID 2450282
 
Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas.
Miller CT, Chen G, Gharib TG, Wang H, Thomas DG, Misek DE, Giordano TJ, Yee J, Orringer MB, Hanash SM, Beer DG.
Oncogene. 2003 Sep 11;22(39):7950-7.
PMID 12970743
 
Molecular and immunohistochemical analysis of signaling adaptor protein Crk in human cancers.
Nishihara H, Tanaka S, Tsuda M, Oikawa S, Maeda M, Shimizu M, Shinomiya H, Tanigami A, Sawa H, Nagashima K.
Cancer Lett. 2002 Jun 6;180(1):55-61.
PMID 11911970
 
CrkIII: a novel and biologically distinct member of the Crk family of adaptor proteins.
Prosser S, Sorokina E, Pratt P, Sorokin A.
Oncogene. 2003 Jul 31;22(31):4799-806.
PMID 12894221
 
Sustained formation of focal adhesions with paxillin in morphological differentiation of PC12 cells.
Rhee S, Lee KH, Kim D, Kwon YK, Kang MS, Kwon H.
Mol Cells. 2000 Apr 30;10(2):169-79.
PMID 10850658
 
CrkI and CrkII function as key signaling integrators for migration and invasion of cancer cells.
Rodrigues SP, Fathers KE, Chan G, Zuo D, Halwani F, Meterissian S, Park M.
Mol Cancer Res. 2005 Apr;3(4):183-94.
PMID 15831672
 
Proline cis-trans isomerization controls autoinhibition of a signaling protein.
Sarkar P, Reichman C, Saleh T, Birge RB, Kalodimos CG.
Mol Cell. 2007 Feb 9;25(3):413-26.
PMID 17289588
 
pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk.
Schaller MD, Parsons JT.
Mol Cell Biol. 1995 May;15(5):2635-45.
PMID 7537852
 
Crk protein binds to PDGF receptor and insulin receptor substrate-1 with different modulating effects on PDGF- and insulin-dependent signaling pathways.
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PMID 9627109
 
CrkI adapter protein modulates cell migration and invasion in glioblastoma.
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Cancer Res. 2003 May 1;63(9):2335-7.
PMID 12727859
 
Both the SH2 and SH3 domains of human CRK protein are required for neuronal differentiation of PC12 cells.
Tanaka S, Hattori S, Kurata T, Nagashima K, Fukui Y, Nakamura S, Matsuda M.
Mol Cell Biol. 1993 Jul;13(7):4409-15.
PMID 8321240
 
C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins.
Tanaka S, Morishita T, Hashimoto Y, Hattori S, Nakamura S, Shibuya M, Matuoka K, Takenawa T, Kurata T, Nagashima K, et al.
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Downstream of Crk adaptor signaling pathway: activation of Jun kinase by v-Crk through the guanine nucleotide exchange protein C3G.
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PMID 9122199
 
Signaling adaptor protein v-Crk activates Rho and regulates cell motility in 3Y1 rat fibroblast cell line.
Tsuda M, Tanaka S, Sawa H, Hanafusa H, Nagashima K.
Cell Growth Differ. 2002 Mar;13(3):131-9.
PMID 11959814
 
Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4.
Wang L, Tabu K, Kimura T, Tsuda M, Linghu H, Tanino M, Kaneko S, Nishihara H, Tanaka S.
Biochem Biophys Res Commun. 2007 Nov 3;362(4):976-81. Epub 2007 Aug 27.
PMID 17825249
 
Adaptor molecule Crk is required for sustained phosphorylation of Grb2-associated binder 1 and hepatocyte growth factor-induced cell motility of human synovial sarcoma cell lines.
Watanabe T, Tsuda M, Makino Y, Ichihara S, Sawa H, Minami A, Mochizuki N, Nagashima K, Tanaka S.
Mol Cancer Res. 2006 Jul;4(7):499-510.
PMID 16849525
 
Overexpression of CRKII increases migration and invasive potential in oral squamous cell carcinoma.
Yamada S, Yanamoto S, Kawasaki G, Rokutanda S, Yonezawa H, Kawakita A, Nemoto TK.
Cancer Lett. 2011 Apr 28;303(2):84-91. Epub 2011 Feb 19.
PMID 21339045
 
Isolation and chromosomal localization of CRKL, a human crk-like gene.
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Citation

This paper should be referenced as such :
Tanaka, S
CRK (v-crk sarcoma virus CT10 oncogene homolog (avian))
Atlas Genet Cytogenet Oncol Haematol. 2012;16(8):521-525.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CRKID40149ch17p13.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(3;11)(p25;p15) ANKRD28/NUP98


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  ABR/CRK (17p13)
YWHAE/CRK (17p13)


External links

Nomenclature
Cards
AtlasCRKID40149ch17p13.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)1398
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


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indexed on : Thu Oct 18 17:32:35 CEST 2018

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