FAM20C
Function
Golgi serine/threonine protein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs and plays a key role in biomineralization of bones and teeth (PubMed:22582013, PubMed:23754375, PubMed:25789606). Constitutes the main protein kinase for extracellular proteins, generating the majority of the extracellular phosphoproteome (PubMed:26091039). Mainly phosphorylates proteins within the Ser-x-Glu/pSer motif, but also displays a broader substrate specificity (PubMed:26091039). Phosphorylates ERO1A, enhancing its activity which is required to maintain endoplasmic reticulum redox homeostasis and for oxidative protein folding (PubMed:29858230, PubMed:34349020). During endoplasmic reticulum stress, phosphorylates P4HB/PDIA1 which induces a functional switch, causing P4HB to change from an oxidoreductase to a molecular chaperone (PubMed:32149426). This is critical to maintain ER proteostasis and reduce cell death under ER stress (PubMed:32149426). Phosphorylation of P4HB also promotes its interaction with ERN1, leading to reduced activity of ERN1, a key sensor for the endoplasmic reticulum unfolded protein response (PubMed:32149426). Required for osteoblast differentiation and mineralization (PubMed:34349020). Phosphorylates casein as well as a number of proteins involved in biomineralization such as AMELX, AMTN, ENAM and SPP1/OPN (PubMed:22582013, PubMed:25789606, PubMed:34349020). In addition to its role in biomineralization, also plays a role in lipid homeostasis, wound healing and cell migration and adhesion (PubMed:26091039).
Involvement in disease
Raine syndrome
RNS
An autosomal recessive osteosclerotic bone dysplasia with neonatal lethal outcome, although some patients survive into childhood. Clinical features include generalized increase in the density of all bones and a marked increase in the ossification of the skull, craniofacial dysplasia and microcephaly.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
N-glycosylation is required for folding.
Autophosphorylated.
Propeptide cleavage by MBTPS1/S1P promotes FAM20C secretion and maximal kinase activity which is essential for efficient osteoblast differentiation and biomineralization.
Sequence Similarities
Belongs to the FAM20 family.
Tissue Specificity
Widely expressed.
Cellular localization
- Golgi apparatus membrane
- Single-pass type II membrane protein
- Secreted
- Endoplasmic reticulum
- Resides in the Golgi apparatus membrane and is secreted following propeptide cleavage (PubMed:34349020). Retained in the endoplasmic reticulum (ER) in response to ER stress where it phosphorylates P4HB (PubMed:32149426).
Alternative names
DMP4, FAM20C, Extracellular serine/threonine protein kinase FAM20C, Dentin matrix protein 4, Golgi casein kinase, Golgi-enriched fraction casein kinase, DMP-4, GEF-CK