The Scribble family in cancer: twentieth anniversary

Abstract

Among the more than 160 PDZ containing proteins described in humans, the cytoplasmic scaffold Scribble stands out because of its essential role in many steps of cancer development and dissemination. Its fame has somehow blurred the importance of homologous proteins, Erbin and Lano, all belonging to the LRR and PDZ (LAP) protein family first described twenty years ago. In this review, we will retrace the history of LAP family protein research and draw attention to their contribution in cancer by detailing the features of its members at the structural and functional levels, and highlighting their shared-but also different-implication in the tumoral process.

Fig. 1. The LAP family is conserved in evolution.

The modules which composed the LAP are: Leucine Rich Repeat (LRR), LAP Specific Domains (LAPSD) and PSD-95/Dlg/ZO-1 (PDZ), and PDZ Binding Motives (PDZ-BMs). Conserved cysteine residues are represented by two red triangles and dual S-Palmitoyl groups as green zigzags. The gray scale bar corresponds to 100 amino-acid residues.

Fig. 2. Structure of LAP domains.

a The Erbin LRR domains were modeled with the Phyre2 software using the PDB4u08 LRR protein (35% identity with Erbin LRRs) as a template. The α-helices and the β-sheets are shown in orange and blue, respectively. b The Scribble PDZ1 domain bound to a β-PIX C-term peptide (turquoise blue) (PDB Scrib: 5VWK) [29] and the Erbin PDZ domain (c) bound to ERBB2 C-terminal peptide (PDB: 1MFG) [30] are represented using the Phyre2 software [127].

Fig. 3. Post-translational modifications in LAP family proteins.

Analysis based on HTP (High Throughput Papers) and LTP (Low Throughput Papers) data available in the Phosphositeplus database. A cut-off of 5 references was set to select the phosphorylation sites.

Fig. 4. Signaling pathways associated to LAP proteins in normal and cancer cells.

The upper panel represents normal polarized epithelial cells, the middle panel migratory epithelial/fibroblastic cells and the lower panel cancer cells. Localization of LAP proteins is pinpointed in each situation. In cancer cells, LAP protein expression can be lost or increased, usually with associated mislocalization.

Fig. 5. Multiple partners and functions are associated with Scribble.

Direct Scribble interactors are in orange (PDZ interactors) and green (ERK interacts with the Scribble C-terminal region) bullets. Indirect and/or functional Scribble interactors are in white bullets. The Scribble-associated functions are in gray boxes.