Cancer, skin disorders

Scar contracture

Scar contracture is a skin condition resulting from second or third degree burn, in which the skin around the burn pulls together and tightens, leading to scar formation and restriction in movement in the area surrounding the injured skin. In mouse and human fibroblasts, FAK expression is necessary for scar formation after wounding. In addition, significantly elevated levels of FAK protein expression was observed in a mouse model of hypertrophic scar formation after cutaneous injury, and mice lacking FAK expression displayed reduced scarring after injury. The downstream targets of FAK activity, MCP-1 and ERK, are also required for scar formation, indicating a key role for FAK signalling in scar formation. In addition, It has been shown that the FAK gene is activated after cutaneous injury and that the activation process is potentiated by the application of mechanical force. Mechanical force acting on tissue regulates cell- extracellular matrix interactions that are mediated through intracellular components of focal adhesions, one of which is the FAK protein. In addition, FAK has been shown to act through the extracellular-regulated kinase (ERK) to stimulate the release of monocyte chemoattractant protein-1 (MCP-1), which is a potent inflammatory cytokine associated with various human fibrotic disorders. Small molecule inhibitors of the FAK protein have been shown to reduce scar formation in human tissues after injury through the reduction of MCP-1 signalling and impaired recruitment of inflammatory cells to the site of injury. Therefore, elevated levels of FAK expression in skin fibroblast after cutaneous injury may contribute to the pathology of scar contracture.
 

Breast cancer; Gastroesophageal junction adenocarcinomas; Askin's tumours

FAK appears to be an oncoprotein (OP). A role for FAK in cancer cell migration and motility has been demonstrated for several human cancer types. Knockdown of FAK expression in a human gastric adenocarinoma cell line resulted in the impairment of cancer cell spreading and elongation, confirming a key role for the FAK protein in the regulation of cancer cell motility and metastasis. The FAK gene has been mapped to chromosome 8 (8q24) and is linked to the MYC gene, a known oncogene. In animal studies, deletion of the FAK gene in mice prevented papilloma formation and inhibited the progression of malignancy in pre-formed benign tumors, indicating an oncogenic role for the FAK protein. Additionally, FAK gene deletion was associated with a reduction in keratinocyte migration and increased keratinocyte cell death. Therefore, FAK was concluded to modulate the formation of benign tumours and their subsequent malignant conversion. In 39 hepatocellular carcinoma (HCC) cell lines analyzed for copy number expression, increased copy number was observed at the FAK locus and correlated strongly with expression level of the FAK protein as well as an increased tumour size (>5 cm).
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Barrett's esophagus epithelial metaplasia (%CFC= +71, p<0.095); Bladder carcinomas (%CFC= +127, p<0.0001); Cervical cancer (%CFC= -60, p<0.0001); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= -91, p<0.0001); Head and neck squamous cell carcinomas (HNSCC) (%CFC= +55, p<0.0007); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +89, p<0.0005); Oral squamous cell carcinomas (OSCC) (%CFC= +66, p<0.008); and Prostate cancer - primary (%CFC= +94, p<0.0001).

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.07 % in 24930 diverse cancer specimens. This rate is only -7 % lower and is very similar to the average rate of 0.075 % calculated for human protein kinases in general.

Most frequent mutations with the number of reports indicated in brackets: F147S (3); F147L (2).

Only 5 deletions, no insertions or complex mutations are noted on the COSMIC website.