The FAM83 family of proteins: from pseudo-PLDs to anchors for CK1 isoforms

Abstract

The eight members of the FAM83 (FAMily with sequence similarity 83) family of poorly characterised proteins are only present in vertebrates and are defined by the presence of the conserved DUF1669 domain of unknown function at their N-termini. The DUF1669 domain consists of a conserved phospholipase D (PLD)-like catalytic motif. However, the FAM83 proteins display no PLD catalytic (PLDc) activity, and the pseudo-PLDc motif present in each FAM83 member lacks the crucial elements of the native PLDc motif. In the absence of catalytic activity, it is likely that the DUF1669 domain has evolved to espouse novel function(s) in biology. Recent studies have indicated that the DUF1669 domain mediates the interaction with different isoforms of the CK1 (casein kinase 1) family of Ser/Thr protein kinases. In turn, different FAM83 proteins, which exhibit unique amino acid sequences outside the DUF1669 domain, deliver CK1 isoforms to unique subcellular compartments. One of the first protein kinases to be discovered, the CK1 isoforms are thought to be constitutively active and are known to control a plethora of biological processes. Yet, their regulation of kinase activity, substrate selectivity and subcellular localisation has remained a mystery. The emerging evidence now supports a central role for the DUF1669 domain, and the FAM83 proteins, in the regulation of CK1 biology.

FAM83A Promotes Lung Cancer Progression by Regulating the Wnt and Hippo Signaling Pathways and Indicates Poor Prognosis

“…Family with sequence similarity 83, member A (FAM83A), also known as bj-tsa-9, is located on chromosome 8q24 and was initially identified as a potential tumor-specific gene using a bioinformatics method (3). It consists of 434 amino acids, including DUF1669, serine-rich, and protein-rich domains (4), and the DUF1669 domain at its N-terminus is thought to be involved in tumor progression (5,6). It has been reported that FAM83A is overexpressed in a variety of human tumors including lung, breast, testicular, and bladder cancers, suggesting that FAM83A may play a carcinogenic role in the development of cancer (7)(8)(9).…”

IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

“…Historically, CK1 isoforms were thought to be monomeric, unregulated and constitutively active but there is now accumulating evidence that a family of previously uncharacterised proteins, the FAM83 proteins, act as anchors for several of the CK1 isoforms (, -like, , and ) and can alter their subcellular localisation in response to specific stimuli (14,15). The FAM83 family is composed of 8 members, termed FAM83A-H, which share a conserved Nterminal domain of unknown function 1669 (DUF1669), which mediates the interaction with different CK1 isoforms (14).…”

FAM 83D directs protein kinase CK 1α to the mitotic spindle for proper spindle positioning

“…However, phosphorylation of distinct substrates by CK1a may trigger their translocation from the spindle to the actin network directly or indirectly. Nonetheless, the findings that the FAM83D-CK1a complex acts at the mitotic spindle add to the evidence for intricate subcellular regulation of CK1 isoforms, which are implicated in many cellular processes from Wnt signalling to the regulation of circadian rhythms, by FAM83 proteins [13]. Given the participation of CK1 isoforms in such diverse biological processes, it is perhaps not surprising that some studies have explored and reported on roles for CK1a in the cell division cycle.…”

“…We recently reported that the FAM83 family of poorly characterised proteins act as subcellular anchors for CK1 isoforms through the conserved N-terminal domain of unknown function 1669 (DUF1669) [12]. Our findings that FAM83 proteins interact and colocalise with different CK1 isoforms offer the tantalising possibility that FAM83 proteins direct CK1 isoforms to specific subcellular compartments, and in doing so, regulate their substrate availability/ accessibility [13]. In line with this, we have shown that FAM83G [(aka protein associated with SMAD1 (PAWS1)] activates Wnt signalling through its association with CK1a [14].…”