A functional network of the tumor suppressors APC, hDlg, and PTEN, that relies on recognition of specific PDZ‐domains

Abstract

APC and PTEN are tumor suppressor proteins that bind through their C-termini to the PDZ domain containing-hDlg scaffolding protein. We have found that co-expression of PTEN and hDlg enhanced the negative regulation of the PI3K/Akt pathway by PTEN, indicating the physiologic importance of these interactions. APC and PTEN share other PDZ domain containing-interacting partners, including the MAGI scaffolding proteins and the MAST family of protein kinases. Mutational analysis revealed that the C-terminal PDZ-binding motifs from APC and PTEN were differentially recognized by distinct PDZ domains. APC bound to the three PDZ domains from hDlg, whereas PTEN mainly bound to PDZ-2/hDlg. This indicates the existence of overlapping, but distinct PDZ-domain recognition patterns by APC and PTEN. Furthermore, a ternary complex formed by APC, PTEN, and hDlg was detected, suggesting that hDlg may serve as a platform to bring in proximity APC and PTEN tumor suppressor activities. In line with this, tumor-related mutations targeting the PDZ-2/hDlg domain diminished its interaction with APC and PTEN. Our results expand the PDZ-domain counterparts for the tumor suppressor APC, show that APC and PTEN share PDZ-domain partners but have individual molecular determinants for specific recognition of PDZ domains, and suggest the participation of the tumor suppressors APC, PTEN, and hDlg in PDZ-domain interaction networks which may be relevant in oncogenesis.

The Scribble–Dlg–Lgl Module in Cell Polarity Regulation

“…Several physical interactions occur between the Scribble polarity module and Wnt signaling components; Lgl and Dsh, in controlling PCP (Dollar et al 2005;Kaplan and Tolwinski 2010;see Sect. 4.4.2); Scrib and β-catenin, implicated in synaptic vesicle trafficking and recycling in neural cells (Sun et al 2009); Dlg or Scrib and APC, important in cell cycle exit and cell migration (Takizawa et al 2006;Sotelo et al 2012;Matsumine et al 1996;Ishidate et al 2000;Etienne-Manneville et al 2005); and Dlg and Fzd, thought to be important in establishing a scaffold in canonical or noncanonical Wnt signaling (Hering and Sheng 2002;Luyten et al 2008). With the exception of the interaction of Lgl with Dsh, all of these studies have been undertaken in mammalian systems, and therefore further studies in invertebrate models are required to explore the universality of these interactions.…”

Disc large 1 expression is altered by human papillomavirus E6/E7 proteins in organotypic cultures of human keratinocytes

“…Most of the biological functions of DLG1 rely on its ability to interact with several regulatory proteins, such as protein 4.1/ERM family members (Lue et al, 1994), several kinases (Gaudet et al, 2000;Sabio et al, 2005;Gaudet et al 2011) and two important tumour suppressors: phosphatase and tensin homologue (PTEN) and adenomatous polyposis coli (APC) (Sotelo et al, 2012). Remarkably, DLG1 : APC binding is important for the negative regulation of cell growth (Ishidate et al, 2000) and the interaction with PTEN is required for PTEN stability, cooperating with the inactivation of the proliferative pathways (Sotelo et al, 2012;Valiente et al, 2005).…”

“…Remarkably, DLG1 : APC binding is important for the negative regulation of cell growth (Ishidate et al, 2000) and the interaction with PTEN is required for PTEN stability, cooperating with the inactivation of the proliferative pathways (Sotelo et al, 2012;Valiente et al, 2005). DLG1 was shown to have a dual role in the regulation of both cell polarity and proliferation, highlighting that tissue polarity and cell cycle should be fine-tuned linked processes during tumour suppression.…”

DLG1 (discs, large homolog 1 (Drosophila))

“…This indicates the existence of overlapping, but distinct PDZ-domain recognition patterns by APC and PTEN. Furthermore, a ternary complex formed by APC, PTEN, and hDlg has been detected, suggesting that hDlg may serve as a platform to bring in proximity APC and PTEN tumor suppressor activities, which may be relevant in oncogenesis (Sotelo et al 2012). In addition, APC appears to mediate the interaction between DLG1, beta-catenin and the actin cytoskeleton.…”