Development - WNT5A signaling

WNT5A signaling

WNT5A is a non-canonical member of WNT family of proteins which controls a number of essential processes in early development. WNT5A acts via the "non-canonical" and, to a smaller degree, "canonical" Wnt signaling pathways [1], [2].

The "non-canonical" pathway involves WNT5A activation of FZD2 and ROR2 [1], [2], [3].

Activated by WNT5A, FZD2 transforms heterotrimeric guanine nucleotide binding protein (G-protein), which dissociates onto G-protein alpha-t2 and G-protein beta/gamma) subunits [4]. Activation of G-protein alpha-t2 leads to PDE6 cat activation (most possibly via G-protein alpha-t2 sequestration of PDE6 reg) [5], [6], [7]. PDE6 cat decreases concentration of Cyclic GMP which leads to the suppression of Protein kinase G1 [8] and activation of IP3R1 on endoplasmic reticulum membrane (probably via removing from IP3R1 inhibitory action of IRAG) [9], [10], [11].

Activation of G-protein beta/gamma, in turn, leads to stimulation of PLC-beta activity, which increases IP3 and 1,2-Diacyglycerol level. IP3 binds to the activated IP3R1 and promotes Ca('2+) release into cytosol [12], [13], [14]. It leads to activation of Ca(2+)-dependent PKC-alpha and promotes neuronal differentiation [14], [15]. Also, increased Ca('2+) levels activate catalytic subunits of Calcineurin A (catalytic) and, subsequently, promote NF-AT1(NFATC2) transcriptional activity [7], [16]. Finally, Ca('2+) activates Calmodulin and CaMK II, which promotes TAK1(MAP3K7) and further NLK activation. NLK phosphorylates transcription factor Tcf(Lef) and, thus, suppresses the canonical WNT pathway [17], [18], [19].

Activation of ROR2 receptor by WNT5A activates PI3K reg class IA (p85) and, subsequently (via unknown Guanine nucleotide exchange factor), CDC42. The activated CDC42 stimulates MKK7 (MAP2K7), most likely via binding to MLK2(MAP3K10), MLK3(MAP3K11), followed by JNK(MAPK8-10) activation. JNK(MAPK8-10) phosphorylates c-Jun and ATF-2 and increases their transcriptional activity, thus stimulating embryonic convergent extension movements [20], [21], [22].

Furthermore, WNT5A-activated ROR2 binds to Filamin A, which is involved in filopodium assembly [23], and can additionally stimulate JNK(MAPK8-10) via connection to MEK4(MAP2K4) and MKK7 (MAP2K7) [24], [25].

WNT5A can also act via the canonical pathway, which involves activation of FZD4, FZD5 receptors and LRP5 co-receptor. The activated FZD4 and FZD5 recruit Dsh to plasma membrane and LRP5 binds and inactivates Axin, which leads to inactivation of GSK3 beta, prevention of Axin binding to Beta-catenin and its stabilization. So, Beta-catenin can bind and stimulate transcriptional activity of Tcf(Lef) [1], [2], [26].

Objects list:

References:

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