Review of PIP2 in Cellular Signaling, Functions and Diseases

Abstract

Phosphoinositides play a crucial role in regulating many cellular functions, such as actin dynamics, signaling, intracellular trafficking, membrane dynamics, and cell-matrix adhesion. Central to this process is phosphatidylinositol bisphosphate (PIP2). The levels of PIP2 in the membrane are rapidly altered by the activity of phosphoinositide-directed kinases and phosphatases, and it binds to dozens of different intracellular proteins. Despite the vast literature dedicated to understanding the regulation of PIP2 in cells over past 30 years, much remains to be learned about its cellular functions. In this review, we focus on past and recent exciting results on different molecular mechanisms that regulate cellular functions by binding of specific proteins to PIP2 or by stabilizing phosphoinositide pools in different cellular compartments. Moreover, this review summarizes recent findings that implicate dysregulation of PIP2 in many diseases.

Keywords: PIP2; Phosphoinositides; actin; diseases; focal adhesion; intracellular trafficking; membrane dynamics.

Figure 1

Isoforms of phosphoinositides. By the action of PIK and phosphatase, phosphatidylinositol (PtdIns) and the three isoforms of PIP2 are formed, as indicated here. The specific action of PI3K I, II III and of the 3-phosphatases are also illustrated.

Figure 2

Role of PIP2 in actin dynamics either by promoting polymerization or inhibiting severing. The figure summarizes gelsolin, profilin, cofilin, Arp2/3, and WASP dynamics in coordination with Rho- ROCK and Rac pathways.

Figure 3

Role of PIP₂ in regulating focal adhesion assembly. Depiction of adhesion molecules talin, vinculin, ezrin, filamin and a-actinin. PIP₂ synergistically binds to both talin and integrin and activates both of them. Talin binds directly to actin or activates vinculin and facilitates its binding to actin. PIP₂ also binds to FERM domain of FAK and binds to vinculin via paxillin. PIP₂ negatively regulates cross-linking activity of filamin and the actin bundle formation mediated by α-actinin.

Figure 4

Histograms of cluster of lipids which is also measured on the vertical axis. Only the unique combination of PI(4, 5)P₂ and Ca²⁺ shows large and growing clusters. The symbol area is proportional to the number of lipids in the cluster (Bradley et al.) [95].

Figure 5

PIP 2 molecules are necessary to recruit MIM I-BAR, which in turn can induce local PIP 2 clustering at its two ends after binding to the membrane (upper panel). Spontaneous bending of lipid membranes can re-distribute PIP 2 molecules to the negatively curved membrane areas (lower panel), which promotes the recruitment of MIM I-BAR and maintaining the curvature [100].

Figure 6

BIN1 mediated membrane tubulation. BAR domain proteins are able to both sense and induce membrane curvature. BIN1 clustering with PIP2 that promote dynamine recruitment and thus forms T- tubule. Binding of dynamin depends upon the amount of PI(4, 5)P₂ and enhanced by BIN1.

Figure 7

PIP₂ is involved in intracellular trafficking and vesicular transport. PIP₂ participates in both clathrin mediated (CCP) and non- clathrin mediated endocytosis. PI(3,5) P₂ is involved in exocytosis whereas PI(4,5) P₂ and PI(3,4) P₂ are involved in endocytic processes.

Figure 8

PIP₃ and MAP kinase pathways synergistically and independently regulates melanoma cancer or any other carcinoma. Ras regulates both PI3 and Akt kinase pathways. In addition, Ras independently regulates BRAF which is also implicated in Akt3 activity depicted in diagram.