WNT/Frizzled signalling: receptor-ligand selectivity with focus on FZD-G protein signalling and its physiological relevance: IUPHAR Review 3

Abstract

The wingless/int1 (WNT)/Frizzled (FZD) signalling pathway controls numerous cellular processes such as proliferation, differentiation, cell-fate decisions, migration and plays a crucial role during embryonic development. Nineteen mammalian WNTs can bind to 10 FZDs thereby activating different downstream pathways such as WNT/β-catenin, WNT/planar cell polarity and WNT/Ca(2+) . However, the mechanisms of signalling specification and the involvement of heterotrimeric G proteins are still unclear. Disturbances in the pathways can lead to various diseases ranging from cancer, inflammatory diseases to metabolic and neurological disorders. Due to the presence of seven-transmembrane segments, evidence for coupling between FZDs and G proteins and substantial structural differences in class A, B or C GPCRs, FZDs were grouped separately in the IUPHAR GPCR database as the class FZD within the superfamily of GPCRs. Recently, important progress has been made pointing to a direct activation of G proteins after WNT stimulation. WNT/FZD and G protein coupling remain to be fully explored, although the basic observation supporting the nature of FZDs as GPCRs is compelling. Because the involvement of different (i) WNTs; (ii) FZDs; and (iii) intracellular binding partners could selectively affect signalling specification, in this review we present the current understanding of receptor/ligand selectivity of FZDs and WNTs. We pinpoint what is known about signalling specification and the physiological relevance of these interactions with special emphasis on FZD-G protein interactions.

Keywords: Dishevelled; Frizzled; GPCR; WNT; heterotrimeric G proteins.

Figure 1

Heterotrimeric G protein α-subunit subfamilies and their effects in WNT/FZD signalling. This figure provides an overview of all 16 heterotrimeric G protein α-subunits, which are categorized according to their Gα subunit (Gα_i, Gα_s, Gα_q and Gα_12/13). In addition, information about specific G α-subunits in direct relation to certain FZDs and WNT proteins is listed.

Figure 2

WNT/FZD interaction. This figure provides an overview of reported WNT/FZD combinations and their possible interaction. Crosses (x) indicate evidence for direct binding based on immunoprecipitation, whereas circles (o) indicate colocalization, signalling outcomes such as TCF reporter activity, TOPflash or internalization. Green indicates data already present in the IUPHAR Database (http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=25). All references can be found within the text or at the IUPHAR Database homepage. Today, all WNTs are available from different companies such as R&D systems, Abcam, ABMGood or Genemed. However, activity and purity of these WNTs should be carefully controlled.