Signaling mechanisms in red blood cells: A view through the protein phosphorylation and deformability

Abstract

Intracellular signaling mechanisms in red blood cells (RBCs) involve various protein kinases and phosphatases and enable rapid adaptive responses to hypoxia, metabolic requirements, oxidative stress, or shear stress by regulating the physiological properties of the cell. Protein phosphorylation is a ubiquitous mechanism for intracellular signal transduction, volume regulation, and cytoskeletal organization in RBCs. Spectrin‐based cytoskeleton connects integral membrane proteins, band 3 and glycophorin C to junctional proteins, ankyrin and Protein 4.1. Phosphorylation leads to a conformational change in the protein structure, weakening the interactions between proteins in the cytoskeletal network that confers a more flexible nature for the RBC membrane. The structural organization of the membrane and the cytoskeleton determines RBC deformability that allows cells to change their ability to deform under shear stress to pass through narrow capillaries. The shear stress sensing mechanisms and oxygenation‐deoxygenation transitions regulate cell volume and mechanical properties of the membrane through the activation of ion transporters and specific phosphorylation events mediated by signal transduction. In this review, we summarize the roles of Protein kinase C, cAMP‐Protein kinase A, cGMP‐nitric oxide, RhoGTPase, and MAP/ERK pathways in the modulation of RBC deformability in both healthy and disease states. We emphasize that targeting signaling elements may be a therapeutic strategy for the treatment of hemoglobinopathies or channelopathies. We expect the present review will provide additional insights into RBC responses to shear stress and hypoxia via signaling mechanisms and shed light on the current and novel treatment options for pathophysiological conditions.

Aging Injury Impairs Structural Properties and Cell Signaling in Human Red Blood Cells; Açaì Berry Is a Keystone

“…Red blood cells flow through circulatory system for 120 days, during which they continuously modify their biconcave shape (8 µm size) to able to traverse blood vessels that narrow to 1 µm size. Deformability of RBCs is, then, an essential biomechanical property to maintain proper blood flow in the microcirculation, in order to allow cells to play out their essential functions [ 29 ]. Changes to membrane and/or cytoskeleton proteins, including post-translational modifications, are probably responsible for the impaired cell deformability associated with oxidative stress and natural aging processes [ 21 , 22 , 57 , 58 , 59 ].…”

“…As mentioned above, protein–protein interactions are modulated by post-translational modifications, mostly by phosphorylation of protein residues which leads to conformational modifications of protein structure [ 29 ]. These data confirm that the phosphorylation of membrane and/or cytoskeletal proteins (e.g., band 3 by Syk kinase) damages their affinity for interacting partners and favors the disassociation of the α- and β-spectrin network, which may create a more flexible or relaxed cytoskeletal structure and a reduction in RBC membrane stability.…”

“…The biophysical properties and distribution of the cytoskeletal proteins are responsible for their normal biconcave shape. The structure of the RBC membrane cytoskeleton is composed of a protein network of mainly spectrin, which maintains RBC geometry by changing shape under the mechanical stress influence [ 28 , 29 ]. The network is characterized by the interaction between spectrin (two heterodimers: α- and β-subunits) anchored to the RBC membrane at two points: the ankyrin complex and the junctional complex, both of which center in band 3 ( Figure 1 ) [ 30 ].…”

“…The network is characterized by the interaction between spectrin (two heterodimers: α- and β-subunits) anchored to the RBC membrane at two points: the ankyrin complex and the junctional complex, both of which center in band 3 ( Figure 1 ) [ 30 ]. Protein–protein interactions are modulated by post-translational modifications, mainly by phosphorylation of tyrosine and/or serine protein residues, leading to conformational changes of protein molecular structure [ 29 , 31 ]. Protein dephosphorylation and phosphorylation play a crucial role to regulate elasticity of the plasma membrane and, in turn, RBC deformability [ 32 , 33 , 34 ].…”

Protein modifications and diseases

“…First, this special issue includes emerge papers focusing on the new substrates and functions of protein phosphorylation in cellular physiology and diseases (Cilek et al, 2023; Han et al, 2023; Javary et al, 2022). As a key posttranslational modification, protein phosphorylation regulates a range of protein functions in almost all cellular processes (Ochoa et al, 2020).…”