PEBP1/RKIP behavior: a mirror of actin-membrane organization

Abstract

Phosphatidylethanolamine-binding protein 1 (PEBP1), a small 21 kDa protein, is implicated in several key processes of the living cell. The deregulation of PEBP1, especially its downregulation, leads to major diseases such as cancer and Alzheimer's disease. PEBP1 was found to interact with numerous proteins, especially kinases and GTPases, generally inhibiting their activity. To understand the basic functionality of this amazing small protein, we have considered several known processes that it modulates and we have discussed the role of each molecular target in these processes. Here, we propose that cortical actin organization, associated with membrane changes, is involved in the majority of the processes modulated by PEBP1. Furthermore, based on recent data, we summarize some key PEBP1-interacting proteins, and we report their respective functions and focus on their relationships with actin organization. We suggest that, depending on the cell status and environment, PEBP1 is an organizer of the actin-membrane composite material.

Keywords: Actin; Cell shape; Cytoskeleton; Membrane; Motility.

Fig. 1

The role of PEBP1-interacting proteins in actin organization. Different types of receptors receive extracellular signals and trigger signaling that aside from phosphorylation cascades result in activation of small GTPases of the Rho family. Activated Rho-GTPases in turn lead to the formation of actin-based protrusions and adhesion and thus induce cell locomotion. The small GTPases are modulated by numerous regulatory proteins, such as guanine-nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Note that for clarity of the figure, the phosphorylation cascades controlled by PEBP1 are not indicated. Note also that there is considerable cross-talk between the Rho-GTPases and several positive and negative feedback loops arising from actin remodeling (they are omitted in the figure for the sake of readability). The main known PEBP1-interacting proteins are highlighted in orange color. They appear to regulate several key points of actin organization from membrane receptors to Rho-GTPases

Fig. 2

3D Structure of wild-type PEBP1 [3]. S153 is known to be the phosphorylation site of PEBP1 by PKC. The side chain of S153 is indicated in green color. Phosphorylated PEBP1 releases Raf1 and binds to GRK2. As seen here, in the wild-type structure, K157 interacts with D134 and E135. On the contrary, the phosphorylated S153 outcompetes D134 and E135 for interaction with K157 and allows the binding of PEBP1 to GRK2 [90]. D134, E135, and K157 are indicated in red, magenta, and blue colors, respectively. The binding site of PEBP1 toward anions is indicated by an acetate ion presented in gold color. The loop consisting of the segment 133–158 of PEBP1 that contains D134, E135, S153, and K157 is well exposed to solvent and, by protein–protein docking, has been identified as a possible interaction zone with Raf1 [91]