Cdc42-binding kinase

Cdc42-binding kinase, also known as myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK), belongs to the DMPK family. Cdc42-binding kinase is an effector protein of Cdc42 and Rac1, a multi-domain protein of about 190kDa. Cdc42-binding kinase contains an N-terminal kinase domain, an intermediate coiled-coil domain, and a C-terminal regulatory domain (including C1, PH, CNH domains, and CRIB motifs). Cdc42-binding kinase exists as a homodimer, and the coiled-coil domain is about 55 nm long, which acts as a "molecular ruler" to locate the distance between the kinase domain and the membrane^[1][2].
There are three subtypes of MRCK in humans: α, β, and γ. α and β are widely expressed, and γ is mainly expressed in muscle tissue. All three contain CRIB motifs and can bind to Cdc42/Rac1. The γ subunit has a preference for TC10^[1][2].
Cdc42-binding kinase promotes actomyosin contraction by phosphorylating myosin regulatory light chain (MLC2) Ser19 and inhibiting myosin phosphatase (MLCP) subunit MYPT1, and participates in the establishment of cell polarity, directional migration, neurite growth, epithelial cell apical contraction, and cancer cell invasion. It can also phosphorylate LIMK1 to stabilize actin fibers.
Mechanistically, Cdc42-binding kinase binds to activated Cdc42-GTP through the CRIB motif, binds to membrane lipids such as phosphatidylserine (PS) with the help of C1 and PH domains, and localizes to the cell membrane; the coiled-coil domain mediates dimerization and maintains the active conformation of the kinase, binds to the actomyosin complex through the adaptor protein LRAP25/35a, such as LRAP35a mediating the binding of MRCK to MYO18A, and regulating the dynamics of lamellipodia actin fibers. At the same time, Cdc42-binding kinase participates in the Cdc42 and Rac1 signaling pathways, and is recruited to specific membrane regions by binding to GTP-formed Cdc42/Rac1, synergistically regulating the reorganization of the actin skeleton^[1][2].
Interacting proteins of Cdc42-binding kinase include small GTPases CDC42 and Rac1, membrane lipids such as PS, inositol bisphosphates (PIPs), adaptor proteins LRAP25/35a, Shroom (ROCK-like adaptor protein), and actin-related proteins MYO18A and LIMK1^[1][2].
Among the inhibitors of Cdc42-binding kinase, BDP5290 (HY-12437) is a selective inhibitor of MRCK, which is more than 50 times more selective for MRCKβ than ROCK and can block cancer cell invasion; Chelerythrine (HY-N2359) inhibits the activity of MRCK by binding to its C1 domain, affecting the formation of sheet-like actin fibers, with an IC₅₀ of 1.8 μM, but there is a non-target effect^[1][2].
In summary, MRCK abnormalities may be closely related to cancer cell migration and invasion, and its inhibitors are potential anticancer drugs. In developmental biology, MRCK is involved in embryonic gastrulation and the establishment of epithelial cell polarity, and its abnormal function may lead to developmental defects; in addition, the specific expression of MRCKγ in muscle tissue suggests that it may be associated with the pathological mechanism of muscle-related diseases such as myotonic dystrophy, but its specific role still needs further study^[1][2].

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