Fig. 2

Kinase-Dependent and kinase-Independent Signaling Pathways Mediated by CRAF. a Role of CRAF in the kinase-dependent signaling pathway. As a cytosolic serine/threonine kinase, CRAF plays an important role in proliferation, migration invasion, EMT invasion, stem cell self-renewal, mitogen and stress-induced signaling responses, and cell apoptosis in the Ras-RAF-MEK-ERK cascade. β-arrestin mediates the active internalization of G protein-coupled receptors (GPCRs) and activates ERK1/2 through CRAF. GPCR also promotes Ca2⁺ mobilization and activation of protein kinase C (PKC) dependent of β-arrestin. Ca2⁺ signaling also promotes cAMP/protein kinase A (PKA) activity. PKA and PKC can activate B/CRAF, promoting the RAF/MEK/ERK MAPK signaling pathway. PKA can also facilitate ERK inhibition by forming an inactive complex with Rap1/CRAF. This complex disrupts the activation of MEK1 and MEK2 by sequestering CRAF activity. Similar to PKA, 14-3-3 proteins also contribute to the inactivation of CRAF. Upon activation of receptor tyrosine kinases (RTKs) by extracellular signals, CRAF dissociates from 14-3-3 and is recruited to the plasma membrane. PI3K-AKT is positioned downstream of RAS and interacts with CRAF through Polycystic Kidney Disease 1 (PKD1). The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF-ERK signaling. CRAF-MEK-ERK signaling pathway regulates numerous targets in the cytoplasm and nucleus, including c-FOS, c-JUN, E2F transcription factor, retinoblastoma protein (Rb), Bcl-2 interacting mediator of cell death (Bim) and Bcl-2 homologous killer (Bak), β-Catenin, Fos-related antigen 1(Fra1), ZEB1/ZEB2, and Pyruvate kinase M2 (PKM2). Glutathione S-transferase pi 1 (GSTP1) inhibits the CRAF pathway through an autocrine feedback loop. In addition, ERK can negatively regulate B/CRAF through the HSP90/ERK1/2/PP5 complex. Furthermore, Transforming Growth Factor-beta (TGF-β) regulates the AP-1-Snail involved in Epithelial-Mesenchymal Transition (EMT) through CRAF-MAPK signaling. b Role of CRAF in the kinase-independent signaling pathway. CRAF plays an important role in mitotic progression by promoting AURKA and Plk1 activation. Mitochondrial membrane-bound CRAF regulates cell apoptosis by recruiting Apoptosis Signal-Regulating Kinase 1 (ASK-1) and Bcl-2 phosphorylate homolog BAD. Moreover, mammalian sterile 20-like kinase (MST2)/Hippo signaling is also involved in anti-apoptotic. CRAF modifies T helper cell differentiation and enhances immune responses by antagonizing Spleen Tyrosine Kinase (Syk)-induced RelB activation. CRAF also induces acetylation of the Nuclear Factor-kappa B (NF-κB) p65 to modulate adaptive immunity by dendritic cells (DCs). Genotoxic stress also induces p21-activated protein kinase-1 (PAK-1) activity, activates CRAF at serine 338, and promotes DNA damage repair independent of MAPK pathway. GFR, Growth Factor Receptor; bFGF, basic Fibroblast Growth Factor; DC-SIGN, Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin; TLR, Toll-like Receptor; TRIF, TIR-domain-containing adapter-inducing interferon-β; NIK, NF-κB-Inducing Kinase