Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway

Abstract

Deviations from the precisely coordinated programme of human head development can lead to craniofacial and orofacial malformations often including a variety of dental abnormalities too. Although the aetiology is still unknown in many cases, during the last decades different intracellular signalling pathways have been genetically linked to specific disorders. Among these pathways, the RAS/extracellular signal-regulated kinase (ERK) signalling cascade is the focus of this review since it encompasses a large group of genes that when mutated cause some of the most common and severe developmental anomalies in humans. We present the components of the RAS/ERK pathway implicated in craniofacial and orodental disorders through a series of human and animal studies. We attempt to unravel the specific molecular targets downstream of ERK that act on particular cell types and regulate key steps in the associated developmental processes. Finally we point to ambiguities in our current knowledge that need to be clarified before RAS/ERK-targeting therapeutic approaches can be implemented.

Erf Affects Commitment and Differentiation of Osteoprogenitor Cells in Cranial Sutures via the Retinoic Acid Pathway

“…Genetic analysis has identified an increasing number of genes that, when mutated, cause craniosynostosis. Activating mutations in three members of the fibroblast growth factor receptor family (FGFR1, FGFR2, FGFR3) and alterations in downstream signalling cascades such as the p38 MAPK, ERK1/2, PI3K/AKT and PLCγ/PKC pathways have been commonly reported to be involved in syndromic cases (8)(9)(10)(11)(12)(13)(14). We previously reported that haploinsufficiency of the ets-domain transcriptional repressor factor ERF, a downstream target of ERKs that can regulate cellular proliferation and differentiation (15)(16)(17)(18), causes premature suture closure in humans (19,20).…”

MAP kinase phosphatase MKP-1 regulates p-ERK1/2 signaling pathway with fluoride treatment

“…The Ras/Raf/MEK/ERK cascade reaction is the key factor in integrating the signal transduction pathway. Previous observation of individuals with orofacial and craniofacial disorders identi ed an association of Ras/Raf/MEK/ERK pathway and dental malformations [14]. MKP-1 has the capacity to bind and dephosphorylate ERK, and subsequently p38 and JNK kinases.…”

The Emerging Role of Interleukin-(IL)-11/IL-11R in Bone Metabolism and Homeostasis: From Cytokine to Osteokine

“…This pathway promotes the activation of Raf kinases, which, in turn, phosphorylate MEK kinases resulting in MAPK activation and subsequent regulation of intracellular targets [30]. Thus, IL-11 is transduced in part through the Ras/Raf/MAPK signaling pathway [30,31]. IL-11 also activates the PI3K/AKT pathway independent of the tyrosine phosphorylation of gp130.…”

“…Administering a high concentration of rhIL-11 promotes the formation of the active GTP-bound form Ras and coupled with the growth factor receptor binding protein 2 (Grb2)/son of sevenless complex, thereby initiating the Ras signaling pathway in adipocytes [ 29 ]. This pathway promotes the activation of Raf kinases, which, in turn, phosphorylate MEK kinases resulting in MAPK activation and subsequent regulation of intracellular targets [ 30 ]. Thus, IL-11 is transduced in part through the Ras/Raf/MAPK signaling pathway [ 30 , 31 ].…”