Liprins in oncogenic signaling and cancer cell adhesion

Abstract

Liprins are a multifunctional family of scaffold proteins, identified by their involvement in several important neuronal functions related to signaling and organization of synaptic structures. More recently, the knowledge on the liprin family has expanded from neuronal functions to processes relevant to cancer progression, including cell adhesion, cell motility, cancer cell invasion, and signaling. These proteins consist of regions, which by prediction are intrinsically disordered, and may be involved in the assembly of supramolecular structures relevant for their functions. This review summarizes the current understanding of the functions of liprins in different cellular processes, with special emphasis on liprins in tumor progression. The available data indicate that liprins may be potential biomarkers for cancer progression and may have therapeutic importance.

Fig. 1. Liprin-α proteins interact with several partners by specific protein–protein interactions.

Liprin-α1 is shown in the drawing. Black arrows show direct interactions between the indicated proteins/protein regions (blue lines; residues in brackets). Ank ankyrin, Arf-GAP GTPase activating protein for Arf GTPases, D1 phosphatase domain, D2 phosphatase–like domain (catalytically inactive), FN-III fibronectin type III, Ig immunoglobulin, PBD paxillin binding domain, PDZ-b, PDZ binding peptide, SAM sterile-alpha motif, SHD Spa2 homology domain, TM transmembrane region. Intrinsically disordered regions were identified by the program DisEMBL [18], coiled coil regions by the program COILS [19].

Fig. 2. PPFIA1 is overexpressed in head and neck and breast cancers.

The figure shows a body-wide gene profile of the PPFIA1 gene across 15392 malignant and 3082 healthy samples. Each dot represents the expression of PPFIA1 gene in one sample. Anatomical origins of each sample are marked with colored bars below the gene plot. Sample types having higher than average expression or an outlier expression profile are additionally colored. The image has been modified from MediSapiens ISTOnline database.

Fig. 3. Contribution of liprins to cancer cell motility and invasive capabilities.

A Simplified model of liprin-α1 contribution to invadosomes and ECM degradation in a context– and cell line–dependent manner. In specific type of cancer cells (on the left) with invadosomes capable of degrading ECM, liprin-α1 is located at the adhesion ring of the invadosome. Liprin-α1 is not necessarily required for ECM degradation per se in these cells, but rather regulates the stabilization and motility of invadosomes. On the right side of the illustration, cross section shows that liprin-α1 is recruited to the invadosome-associated compartments. Cortactin, actin, focal adhesion proteins (such as paxillin, vinculin, and talin) and integrins are recruited to the invadosome, where MMPs play a crucial role in ECM degradation. B Model for the interplay between PMAPs and focal adhesions. PMAPs are observed near dynamic focal adhesions at the front of migrating tumor cells, where PMAP proteins are required to promote focal adhesion turnover. A possible link between focal adhesions and PMAPs are represented by the KANK proteins that can interact both with the focal adhesion protein talin, and PMAP proteins liprin beta. PMAPs also link adhesions to the cytoskeleton via PMAP components interacting either with actin or with microtubules.