PTK7 localization and protein stability is affected by canonical Wnt ligands

Abstract

Protein tyrosine kinase 7 (PTK7) is an evolutionarily conserved transmembrane receptor with important roles in embryonic development and disease. Originally identified as a gene upregulated in colon cancer, it was later shown to regulate planar cell polarity (PCP) and directional cell movement. PTK7 is a Wnt co-receptor; however, its role in Wnt signaling remains controversial. Here, we find evidence that places PTK7 at the intersection of canonical and non-canonical Wnt signaling pathways. In presence of canonical Wnt ligands PTK7 is subject to caveolin-mediated endocytosis, while it is unaffected by non-canonical Wnt ligands. PTK7 endocytosis is dependent on the presence of the PTK7 co-receptor Fz7 (also known as Fzd7) and results in lysosomal degradation of PTK7. As we previously observed that PTK7 activates non-canonical PCP Wnt signaling but inhibits canonical Wnt signaling, our data suggest a mutual inhibition of canonical and PTK7 Wnt signaling. PTK7 likely suppresses canonical Wnt signaling by binding canonical Wnt ligands thereby preventing their interaction with Wnt receptors that would otherwise support canonical Wnt signaling. Conversely, if canonical Wnt proteins interact with the PTK7 receptor, they induce its internalization and degradation.

Variants identified in PTK7 associated with neural tube defects

“…PTK7 was reported to interact with Wnt genes and inhibit canonical Wnt signaling (Peradziryi et al, ). A recent study reported that PTK7 protein level is regulated by its lysosomal degradation (Berger, Breuer et al, ). We hypothesized that the reduced expression level of the p.Arg630Ser variant might be secondary to its reduced protein stability, since both lysine and arginine are involved in the ubiquitin dependent protein degradation process.…”

Targeting Wnt signaling pseudokinases in hematological cancers

“…PTK7 recruits DVL to the plasma membrane, channeling DVL signaling toward the PCP pathway via Frizzled‐7 . PTK7 was shown to interact with ROR2 and Wnt5a or Wnt3a in order to activate non‐canonical and inhibit canonical Wnt signaling, although more studies are needed to understand its specific interaction and functional roles within Wnt pathway regulation …”

“…62 PTK7 was shown to interact with ROR2 and Wnt5a or Wnt3a in order to activate non-canonical and inhibit canonical Wnt signaling, although more studies are needed to understand its specific interaction and functional roles within Wnt pathway regulation. [63][64][65] Within the hematopoietic tissue, PTK7 expression appears to be limited to immature B-cell precursors in bone marrow and immature T cells (CD4 + recent thymic emigrants (RTEs)). 12,66,67 PTK7 + CD4 + RTEs are direct descendants of thymocytes with a relatively short life due to their conversion into PTK7 − naive CD4 + T cells or their loss by cell death.…”

Impact of Wnt signals on human intervertebral disc cell regeneration

“…Another recent study has provided evidence that several non‐canonical signals in the liver, including WNT5A, can act as antagonists to Wnt3A‐induced β‐catenin/T‐cell factor (TCF) signaling to promote tissue differentiation, suggesting non‐canonical signals can “fine‐tune” the effects of canonical Wnt signaling . Additionally, studies which can uncover further regulatory intricacies and the crosstalk between canonical and non‐canonical Wnt pathways would be beneficial; for example, recent studies have demonstrated that canonical suppression can occur through protein tyrosine kinase 7 (PTK7), as well as crosstalk with the Smad/TGF‐β pathway, known to promote differentiation.…”