Raf kinase

Raf kinase
250px Structure of Raf kinase
Identifiers
EC number	2.7.11.1
CAS number	116485-63-5
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

Raf kinase is a family of serine/threonine-specific protein kinases that play a critical role in the MAPK/ERK signaling pathway. This pathway is essential for regulating cell division, differentiation, and secretion. Raf kinases are involved in transmitting signals from the cell membrane to the nucleus, influencing gene expression and cell fate decisions.

Structure

Raf kinases are composed of three main isoforms: A-Raf, B-Raf, and C-Raf (also known as Raf-1). Each isoform has a conserved structure consisting of three main regions:

• The N-terminal regulatory domain, which contains the Ras-binding domain (RBD) and the cysteine-rich domain (CRD).
• The kinase domain, which is responsible for the enzyme's catalytic activity.
• The C-terminal region, which is involved in protein-protein interactions and regulation of kinase activity.

Function

Raf kinases are activated by Ras proteins, which are small GTPases that act as molecular switches. Upon activation by Ras, Raf kinases phosphorylate and activate MEK1/2, which in turn phosphorylate and activate ERK1/2. This cascade of phosphorylation events leads to the activation of various transcription factors and other proteins that regulate cell proliferation, survival, and differentiation.

Clinical Significance

Mutations in the B-Raf isoform, particularly the V600E mutation, are implicated in various cancers, including melanoma, colorectal cancer, and thyroid cancer. This mutation leads to constitutive activation of the MAPK/ERK pathway, promoting uncontrolled cell growth and survival. As a result, B-Raf inhibitors, such as vemurafenib and dabrafenib, have been developed as targeted therapies for cancers harboring B-Raf mutations.

Research and Development

Ongoing research is focused on understanding the precise mechanisms of Raf kinase regulation and the development of novel inhibitors that can overcome resistance to current therapies. Additionally, the role of Raf kinases in non-cancerous diseases, such as cardiovascular disease and neurodegenerative disorders, is an area of active investigation.

Also see

• MAPK/ERK pathway
• Ras protein family
• Protein kinase
• Signal transduction