Disease relevance of CDC42BPA

• Myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) is a Cdc42-binding serine/threonine kinase with multiple functional domains [1].
• Two PK428 mRNAs 10 and 3.8 kilobase pairs in size are seen in a number of cell lines, including hematopoietic and breast cancer cells [2].

High impact information on CDC42BPA

• Cdc42-MRCK and Rho-ROCK signalling cooperate in myosin phosphorylation and cell invasion [3].
• By contrast, in rounded ROCK-dependent movement, where MLC2 phosphorylation is higher, MRCK has a smaller role [3].
• We provide evidence that the N terminus-mediated dimerization and activation of MRCK and the negative autoregulatory kinase-distal CC interaction are two mutually exclusive events that tightly regulate the catalytic state of the kinase [1].
• MRCK kinase activity was also elevated when cells were treated with phorbol ester, which can interact directly with a cysteine-rich domain next to the distal CC domain [1].
• One such antibody, MANDM1, was used to isolate two related protein kinases, MRCK alpha and beta, from a human brain cDNA library and the shared epitope was located at the catalytic site of DMPK using a phage-displayed random peptide library [4].

Biological context of CDC42BPA

• We therefore suggest that binding of phorbol ester to MRCK releases its autoinhibition, allowing N-terminal dimerization and subsequent kinase activation [1].
• Genomic organization of human myotonic dystrophy kinase-related Cdc42-binding kinase alpha reveals multiple alternative splicing and functional diversity [5].
• Microinjection of plasmid encoding MRCK alpha resulted in actin and myosin reorganization [6].
• The gene corresponding to the 3.8-kb PK428 mRNA, and its corresponding 65-kDa protein, was isolated by polymerase chain reaction screening of a P1 phage human genomic library [2].

Anatomical context of CDC42BPA

• MRCK alpha and Cdc42V12 colocalize, particularly at the cell periphery in transfected HeLa cells [6].
• Northern blots demonstrate that PK428 mRNA is distributed widely among tissues and is expressed at the highest levels in pancreas, heart, and skeletal muscle, with lower levels in liver and lung [2].
• An antibody generated to a glutathione S-transferase-PK428 fusion protein detects a 65-kDa protein in these cell lines, and a similarly sized protein when the cloned cDNA is transiently expressed in Cos 7 cells [2].

Associations of CDC42BPA with chemical compounds

• In addition, immunoprecipitates of the PK428 protein kinase also phosphorylated histone H1 and a peptide encoding a cyclic AMP-dependent protein kinase substrate [2].
• We conclude that additional structural elements within the MRCK structure are necessary if the C1 domains of MRCK are to respond to phorbol ester at concentrations comparable with those that modulate PKC [7].

Analytical, diagnostic and therapeutic context of CDC42BPA

• Immunoprecipitation of the transiently expressed PK428 protein and incubation with [gamma-32P]ATP demonstrate that it is capable of autophosphorylation [2].

References