Paraxial protocadherin coordinates cell polarity during convergent extension via Rho A and JNK

Abstract

Convergent extension movements occur ubiquitously in animal development. This special type of cell movement is controlled by the Wnt/planar cell polarity (PCP) pathway. Here we show that Xenopus paraxial protocadherin (XPAPC) functionally interacts with the Wnt/PCP pathway in the control of convergence and extension (CE) movements in Xenopus laevis. XPAPC functions as a signalling molecule that coordinates cell polarity of the involuting mesoderm in mediolateral orientation and thus selectively promotes convergence in CE movements. XPAPC signals through the small GTPases Rho A and Rac 1 and c-jun N-terminal kinase (JNK). Loss of XPAPC function blocks Rho A-mediated JNK activation. Despite common downstream components, XPAPC and Wnt/PCP signalling are not redundant, and the activity of both, XPAPC and PCP signalling, is required to coordinate CE movements

PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer

“…It will be interesting to dissect the intracellular signals that PCDH8 regulates in breast epithelial cells. Inactivating PCDH8 appears to be an early step in breast tumor progression that may be related to its role in regulating cellular polarity and tissue organization during vertebrate embryogenesis (Hukriede et al, 2003;Medina et al, 2004;Unterseher et al, 2004). Given its high frequency of inactivation, it is likely to represent a key step in the evolution of breast epithelial malignancy.…”

“…Two members of the protocadherin family (protocadherin-10 and -20) are frequently silenced in carcinomas of the nasopharynx and lung due to promoter methylation and inhibit cell migration and proliferation (Imoto et al, 2006;Ying et al, 2006). Paraxial protocadherin (PAPC) is capable of homotypic binding and is a critical mediator of blastocyst somite organization, cell movement and cell polarity during embryogenesis, but its involvement in cancer development is not known (Kim et al, 1998(Kim et al, , 2000Rhee et al, 2003;Unterseher et al, 2004). Given the importance of PAPC in vertebrate development, we decided to evaluate its human ortholog PCDH8 for a role in tumor progression after finding a homozygous deletion of the gene in a breast cancer cell line.…”

Structural and Functional Characterization of the Wnt Inhibitor APC Membrane Recruitment 1 (Amer1)

“…Injection amounts were 10 pg of XWnt8 RNA and 200 pg of hAmer1, hAmer1⌬N, and hAmer1(7Lys). Embryos were obtained by in vitro fertilization and cultured as described previously (31). Embryos were injected at the four-cell stage in both ventral blastomeres, cultured until they reached stage 24 -26 according to the normal table of Nieuwkoop and Faber (32), and scored for the presence of a secondary body axis.…”

Amer2 Protein Is a Novel Negative Regulator of Wnt/β-Catenin Signaling Involved in Neuroectodermal Patterning

“…Protein levels were quantified using AIDA Image Analyzer Version 3.52 (Raytest). For Xenopus experiments, Western blotting was carried out as reported (17).…”