Initiation of focal adhesion assembly by talin and kindlin: A dynamic view

Abstract

Focal adhesions (FAs) are integrin‐containing protein complexes regulated by a network of hundreds of protein–protein interactions. They are formed in a spatiotemporal manner upon the activation of integrin transmembrane receptors, which is crucial to trigger cell adhesion and many other cellular processes including cell migration, spreading and proliferation. Despite decades of studies, a detailed molecular level understanding on how FAs are organized and function is lacking due to their highly complex and dynamic nature. However, advances have been made on studying key integrin activators, talin and kindlin, and their associated proteins, which are major components of nascent FAs critical for initiating the assembly of mature FAs. This review will discuss the structural and functional findings of talin and kindlin and their immediate interaction network, which will shed light upon the architecture of nascent FAs and how they act as seeds for FA assembly to dynamically regulate diverse adhesion‐dependent physiological and pathological responses.

Talin‑1 interaction network in cellular mechanotransduction (Review)

“…When PIP2 binds to Talin-1, it induces a change in the conformation of the Talin-1 head domain, further leading to the unmasking of the integrin-binding site (Fig. 1c) (89). By contrast, the F3 domain of Talin-1 has been reported to directly bind to the integrin β cytoplasmic tail through the same PTB domain.…”

“…1A). Mutations interfering with either Rap1/Talin-1-F0 or Rap1/Talin-1-F1 interaction lead to impaired FA assembling, decreased integrin activation in cHO cells and malfunctioning leukocytes and platelets in mouse models (89). In case both interactions are disrupted, more severe defects in FA assembly, cell spreading and adhesion may be observed (60,(85)(86)(87)(88).…”

“…By contrast, the F3 domain of Talin-1 has been reported to directly bind to the integrin β cytoplasmic tail through the same PTB domain. Even though PIPKIγ may appear to impede Talin-1 F3 PTB domain binding to integrin, it has been reported that PIPKIγ requires only small quantities of Talin-1, being abundant in cells, to be recruited (89). As a kinase, the concentration of PIPKIγ has been reported to be usually decreased (102).…”

Talin in mechanotransduction and mechanomemory at a glance

“…This contrasts with other cytoskeletal linker proteins, such as filamin, which varies greatly in length (Light et al, 2012). Through gene duplication, talin has also given rise to kindlin family proteins, which contain a FERM domain but lack the rod (Ali and Khan, 2014;Meller et al, 2015) and play a key role in integrin activation (Plow and Qin, 2019;Zhu et al, 2021), as well as the actin regulatory protein talin rod domain containing protein 1 (TLNRD1) (Cowell et al, 2021). Although many helical bundles exist in nature, the talin rod fold, comprised of a five-helix bundle, appears to be unique to talins and TLNRD1.…”

TLN2 functions as a tumor suppressor in clear cell renal cell carcinoma via inactivation of the Wnt/β-catenin signaling pathway

“…Numerous studies have focused on this signaling pathway in a variety of human cancers, including ccRCC (13). Talin is a macromolecular cytoskeleton protein located on the extracellular matrix (ECM) that can bind to a variety of adhesion molecules (e.g., integrin, actin, and adhesion kinase) (14). Talin is also an important component of focal adhesion (FA) plaque, which can activate the integrin/FA kinase signaling pathway by activating integrin, thereby affecting tumor metastasis and recurrence (15).…”