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FLASH GENE

Symbol

CRKL

contributors: mct/npt/pgu - updated : 15-01-2020

HGNC name	v-crk sarcoma virus CT10 oncogene homolog (avian)-like
HGNC id	2363

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	22q11.21      Physical location : 21.271.713 - 21.308.037
Synonym name	Crk-like protein

DNA

TYPE	functioning gene
STRUCTURE	36.32 kb     3 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

regionally located

centromeric of the chronic myelogenous leukemia breakpoint region

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005207 3 - 5336 NP_005198 33 303 - 2009 1930730

EXPRESSION

Type

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth tongue     moderately   stomach       highly Endocrine parathyroid       highly Hearing/Equilibrium ear       moderately Lymphoid/Immune lymph node       moderately   thymus       moderately Nervous nerve       moderately Reproductive female system uterus     moderately   male system prostate     moderately Urinary bladder       moderately Visual eye       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow     moderately

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	one SH2 domain
	two SH3 domains

conjugated

PhosphoP

mono polymer

homomer , dimer

HOMOLOGY

interspecies	homolog to murine Crkl (96.7 pc)
	homolog to rattus Crkl (96.7 pc)

intraspecies

homolog to CRK

Homologene

FAMILY

CRK adapter protein family

CATEGORY

adaptor , protooncogene

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm
text	nuclear signaling protein

basic FUNCTION	activating the RAS and JUN kinase signaling pathways
	transforming fibroblasts in a RAS-dependent fashion
	adapter protein functioning in signal transduction, best known as a substrate of the BCR-ABL kinase in chronic myelogenous leukemia
	playing a role in fibroblast transformation by BCR-ABL
	may mediate the transduction of intracellular signals
	permits cells to bypass the strict need for adhesion in response to FGF8 through direct interaction with receptor
	CRK and CRKL adaptor proteins play important roles in numerous signaling pathways, bridging tyrosine kinase substrates to downstream signaling effectors by virtue of their phosphotyrosine-binding SH2 domains and their effector-binding SH3 domains
	regulates head and neck squamous cell carcinoma-cell growth, motility, and integrin-dependent cell adhesion, suggesting that CRKL plays a principal role in HNSCC tumorigenicity
	significant role for CRKL in regulating cell motility
	has the ability to regulate gastric cell proliferation
	involved in signal transduction from multiple tyrosine kinase receptors
	cytoskeletal adaptor protein, having crucial roles in multiple biological processes, including cell proliferation, adhesion, and migration
	CRK and CRKL have overlapping functions that are critical for maintaining cell structure, and have critical roles in cell structure and motility by maintaining cytoskeletal integrity 0)
	CRK, CRKL were required for effector T cell trafficking into sites of inflammation, but not for migration to lymphoid organs
	CRK and CRKL play essential overlapping roles in fibroblast growth
	CRK and CRKL play overlapping roles downstream of FGF signaling in order to regulate lens fiber cell elongation
	signaling adaptor CRKL that might integrate the external and intrinsic cellular signals and coordinate the dynamic activation of cellular signaling pathways including alternative splicing regulation
	CRKL, UBASH3A, and AIFM3 were detected in all phases of kidney development which implies their role as renal development control genes

CELLULAR PROCESS

cell communication

PHYSIOLOGICAL PROCESS

development

text	heart development
	organ morphogenesis
	parathyroid gland development
	thymus development

PATHWAY

metabolism

signaling

signal transduction

	JNK cascade
	intracellular signaling cascade
	CRKL-MAPK pathway might be important in human cardiac development and disease

a component

INTERACTION

DNA

RNA

small molecule

protein	interacting with INPP5D/SHIP1
	interacting with DOCK2 and EPOR
	interacting with phosphorylated CBLB
	specific interaction between phosphorylated Y463 in FGFR1 with the CRKL SH2 domain
	Sprouty1 and Sprouty2 bind to the adaptor protein CRKL in a stimulus-dependent manner (Satoh 2010)
	with CRK have been proposed to interact with tyrosine phosphorylated DAB1 to mediate downstream events in the Reelin pathway
	interaction with CRK, and DOK7 (critical role for CRK and CRKL downstream from DOK7 in presynaptic and postsynaptic differentiation)(
	association of ESR1 and CRKL directly enhances the tumorigenic potential of CRKL, thus pointing to its role in cell proliferation
	CRKL adaptor protein associating with PTPN6 (association is due to CRKL binding to PxxP domains located at AA residues 158-161 within the PTPN6 C-terminal SH2 domain, and AA residues 363-366 within its phosphatase domain)
	CRKL signaling was associated with SRC family kinase (SFK) signaling, specifically with YES1 kinase
	promotes CASP8 recruitment to the peripheral spreading edge of cells, and that the catalytic domain of CASP8 directly interacts with the SH2 domain of CRKL
	DOK1 adaptor is the key effector for the enhancement of CRKL transformation by ABLinhibition
	CRKL mediates PIK3CB-dependent PI3K signaling in PTEN-deficient cancer cells
	IL7 stimulation induced the phosphorylation of the proteins STIP1, ATIC and HNRNPH1, involved in pathways related to survival, proliferation and gene expression, respectively, and increased the phosphorylation of CRKL
	interactions of PIK3AP1 with Src homology 2 (SH2) and SH3 domain-containing adaptor proteins, notably growth factor receptor-bound protein 2 (GRB2) and CRKL

cell & other

REGULATION

Phosphorylated by

BCR-ABL tyrosine kinase in chronic myelogenous leukemia patients

Other

phosphorylated when overexpressed

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   amplification --over   contribute to diverse oncogenic phenotypes in lung cancer, with implications for targeted therapy, and highlight a role of adapter proteins as primary genetic drivers of tumorigenesis tumoral     --over   correlated with progression and malignant proliferation of breast cancers constitutional     --other   haploinsufficiency of CRKL could be responsible for the etiology of conotruncal heart defects (CTDs) in individuals with nested distal deletions and might act as a genetic modifier of individuals with the typical 3 Mb deletion constitutional     --low   in patients with partial DiGeorge syndrome is associated with impairment of T-cell functions tumoral     --over   in human pancreatic cancers and contributed to pancreatic cancer cell proliferation and invasion through ERK signaling

Susceptibility

Variant & Polymorphism

Candidate gene	DEL22Q11
Marker	may be a potential molecular target for head and neck squamous cell carcinoma (HNSCC) diagnosis
	may serve as a novel prognostic biomarker in gastric cancer
	has the potential to serve as a diagnosis and prognosis marker in colon cancer
Therapy target
	System Type Disorder Pubmed cancer head and neck   novel therapeutic strategies as well as CRK cancer digestive stomach has the potential to serve as a molecular therapy target for gastric cancer cancer digestive colon therapy target of colon cancer

ANIMAL & CELL MODELS

mice homozygous for a null mutation exhibit defectsin multiplecranial and cardiac neural crestderivatives, similar to the clinical manifestations of DG/VCFS