Cell matrix adhesions in cancer: The proteins that form the glue

Abstract

The main purposes of Integrin-mediated cell contacts are to interpret bi-directional signals between the extracellular environment and intracellular proteins, as well as, anchor the cell to a matrix. Many cell adhesion molecules have been discovered with a wide spectrum of responsibilities, including recruiting, activating, elongating, and maintaining. This review will perlustrate some of the key incidences that precede focal adhesion formation. Tyrosine phosphorylation is a key signaling initiation event that leads to the recruitment of multiple proteins to focal adhesion sites. Recruitment and concentration of proteins such as Paxillin and Vinculin to Integrin clutches is necessary for focal adhesion development. The assembled networks are responsible for transmitting signals back and forth from the extracellular matrix (ECM) to Actin and its binding proteins. Cancer cells exhibit highly altered focal adhesion dynamics. This review will highlight some key discoveries in cancer cell adhesion, as well as, identify current gaps in knowledge.

Keywords: cancer; focal adhesions; integrins.

Figure 1. Protein recruitment to future FA site

(A) Detached FAs typically have inactivated Integrins, as well as inactive FAK and Src kinases. (B) FAK phosphorylation at Y397 leads to the activation of Src. In the early events of FA formation, localization of Src and FAK to FA sites results in Paxillin phosphorylation at tyrosines 118 and 31.

Figure 2. Vinculin and Paxillin binding

Vinculin is a direct binding partner of Paxillin, Talin, Arp2/3, Actin and the Ena/VASP proteins. Paxillin binds to PYK2, Integrin, Src, Tubulin and PTPN12. The LIM2 and LIM3 domains of Paxillin are necessary for FA targeting.

Figure 3. The three stages of filament assembly

Actin filament assembly requires three stages: a nucleation, elongation and steady state phase. (A) During nucleation, the Actin monomers are converted to stable multimers through nucleating proteins such as Arp2/3. (B) During elongation, monomers are rapidly added to each end. (C) During the steady state phase, WAVE and Ena/VASP interact to enhance Arp2/3 filament assembly.

Figure 4. Microscopic visualization of FAs

Primary tumor cells isolated from MMTV-PyMT tumors were plated on a Fibronectin-coated cover slip and labeled with Vinculin (green) to visualize FAs and DAPI (blue) to visualize the nucleus. Phalloidin (red) staining is shown in the right panel. Scale bar: 10μm.

Figure 5. Key proteins are localized to mature FAs

Diverse proteins participate in FA signaling, including tyrosine kinases, phosphatases, G-Actin binding proteins, and GTPases. A mature FA will contain activate Integrins that are bound to their ECM ligand. FA signaling pathways regulate the activation of these Integrins.