ILK: a pseudokinase in the center stage of cell-matrix adhesion and signaling

Abstract

Integrin-linked kinase (ILK) is a widely expressed and evolutionally conserved component of cell-extracellular matrix (ECM) adhesions. Although initially named as a kinase, ILK contains an unusual pseudoactive site that is incapable of catalyzing phosphorylation. Instead, ILK acts as a central component of a heterotrimer (the PINCH-ILK-parvin complex) at ECM adhesions mediating interactions with a large number of proteins via multiple sites including its pseudoactive site. Through higher level protein-protein interactions, this scaffold links integrins to the actin cytoskeleton and catalytic proteins and thereby regulates focal adhesion assembly, cytoskeleton organization and signaling. This review summarizes recent advances in our understanding of the structure and functions of the PINCH-ILK-parvin complex, and discusses emerging new features of the molecular mechanisms by which it regulates diverse cellular, physiological and pathological processes.

Figure 1

Summary of IPP interactome. This figure depicts PINCH-, ILK- or parvin-mediated interactions of which functions have been investigated. Many of the IPP binding proteins have been listed in previous reviews [10, 27] except the recently published ones including IQGAP1 [43], PP1α [56], WT-1 [58], Ospe [59], LIM8/9 and UNC-95 [60], and Lnk [61].

Figure 2

Pseudoactive site features of ILK: A non-degraded ATP is bound to ILK KLD but its g-phosphate is oriented far away from A319 (see the dotted red line) – a site corresponding to the conventional catalytic base Asp. The typical DFG is replaced by DVK where K341 forms the salt-bridge with the g-phosphate of ATP, facilitating its distinct orientation. In addition to A319 that replaces the conventional catalytic Asp, multiple other catalytically important residues are missing including N321 that replaces Lys and S324 that replaces Asn. These catalytic residues are labeled and their corresponding catalytic residues are provided in the parentheses. Note that there are no surrounding residues that may alternatively substitute these catalytic residues. A single magnesium (cyan) is present in ILK KLD but coordinated differently in contrast to the two magnesium ions present in the conventional kinases. Finally, the activation segment (solid orange line) of ILK KLD is much shorter than the conventional one (dotted orange line).

Figure 3

A proposed structural assembly of IPP and its connection to integrin and actin filaments, allowing the linkage of ECM with actin cytoskeleton. The landscape was created using various PDB coordinates including the integrin extracellular domain (3FCU), integrin transmembrane-cytoplasmic domain (2KNC), ILK KLD/parvin CH2 complex (3KMW), ILK ARD/PINCH LIM1 complex (2KBX), PINCH LIM4 (1NYP), and Parvin CH2 (2K2R).