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CRK-LIKE PROTOONCOGENE, ADAPTOR PROTEIN; CRKL

CRK-LIKE PROTOONCOGENE, ADAPTOR PROTEIN; CRKL

Alternative titles; symbolsV-CRK AVIAN SARCOMA VIRUS CT10 ONCOGENE HOMOLOG-LIKEONCOGENE CRKLHGNC Approved Gene Symbol: CRKLCytogenetic location: 22q11.21 Gen...

Alternative titles; symbols

V-CRK AVIAN SARCOMA VIRUS CT10 ONCOGENE HOMOLOG-LIKE
ONCOGENE CRKL

HGNC Approved Gene Symbol: CRKL

Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:20,917,406-20,953,746 (from NCBI)

▼ Cloning and Expression
CRK (164762) was originally identified as an oncogene transduced by the avian sarcoma virus CT10. Ten Hoeve et al. (1993) identified and characterized a gene, which they called CRKL for CRK-like, from a human K562 lambda gt10 cDNA library. CRKL encodes a 303-amino acid polypeptide with a predicted molecular mass of 36 kD. While CRKL is not the human homolog of CRK, it is similar to protein-tyrosine kinases with SH2 and SH3 (src homology) domains.

▼ Gene Function
Senechal et al. (1996) showed that CRKL becomes phosphorylated when overexpressed, activates Ras-dependent and JNK (601158) pathways, and transforms fibroblasts. The authors also found CRKL to be a substrate for the BCR-ABL tyrosine kinase (ABL; 189980), leading them to conclude that CRKL is a tyrosine kinase and an oncogene.

Sasahara et al. (2002) showed that the adaptor protein CRKL binds directly to WIP (602357) and that, following T-cell receptor ligation, a CRKL-WIP-WASP (300392) complex is recruited by ZAP70 (176947) to lipid rafts and immunologic synapses.

Since Fgf8 (600483) deletion in mice, like Crkl deletion, results in many of the phenotypic features of DiGeorge syndrome (DGS; 188400)/velocardiofacial syndrome (VCFS; 192430), Moon et al. (2006) investigated whether Crkl mediates Fgf8 signaling. In addition to finding interactions between Crkl and Fgf8 during the development of structures affected in DGS/VCFS, Moon et al. (2006) found that Fgf8 induced tyrosine phosphorylation of Fgfr1 (136350) and Fgfr2 (176943) and their binding to Crkl. Crkl was required for normal cellular responses to Fgf8, including survival and migration, Erk (see MAPK3; 601795) activation, and target gene expression.

Hallock et al. (2010) found that Crk and Crkl were recruited to mouse skeletal muscle synapses and played redundant roles in synaptic differentiation. Crk and Crkl bound the same tyrosine-phosphorylated sequences in Dok7 (610285), a protein that functions downstream of agrin (AGRN; 103320) and muscle-specific receptor kinase (MUSK; 601296) in synapse formation.

▼ Mapping
By fluorescence in situ hybridization, ten Hoeve et al. (1993) localized the CRKL gene to chromosome 22q11, centromeric of the chronic myelogenous leukemia breakpoint region.

▼ Molecular Genetics
In a search for genetic drivers of kidney defects in DiGeorge syndrome, Lopez-Rivera et al. (2017) found that the main driver of renal disease was a 370-kb region containing 9 genes. In zebrafish embryos, an induced loss of function in snap29 (604202), aifm3 (617298), and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Lopez-Rivera et al. (2017) concluded that a recurrent 370-kb deletion in the 22q11.2 locus is the driver of kidney defects in DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the 9 genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver.

▼ Animal Model
Since the CRKL gene maps within the common deletion region for DGS/VCFS, Guris et al. (2001) created mice homozygous for a targeted null mutation at the Crkl locus (symbolized Crkol in mice) and found that they exhibited defects in multiple cranial and cardiac neural crest derivatives including the cranial ganglia, aortic arch arteries, cardiac outflow tract, thymus, parathyroid glands, and craniofacial structures. They showed that the migration and early expansion of neural crest cells was unaffected in Crkol -/- embryos. These results therefore indicated an essential stage- and tissue-specific role for Crkol in the function, differentiation, and/or survival of neural crest cells during development. The similarity between the Crkol -/- phenotype and the clinical manifestations of DGS/VCFS implicated defects in CRKL-mediated signaling pathways as part of the molecular mechanism underlying this syndrome.

Guris et al. (2006) found that compound heterozygosity for null alleles of the mouse Crkl and Tbx1 (602054) genes recapitulated thymic, parathyroid, and cardiovascular defects characteristic of DGS at a penetrance far greater than that generated by heterozygosity of Crkl or Tbx1 alone.

Hallock et al. (2010) found that knockout of both Crk and Crkl in mouse skeletal muscle, but not of either gene alone, caused perinatal lethality. Lungs from Crk- and Crkl-deficient newborns failed to expand. Embryonic day-18.5 muscle from Crk- and Crkl-deficient mice lacked innervation and showed severe defects in presynaptic and postsynaptic differentiation.

Tags: 22q11.21