A Review on Adducin from Functional to Pathological Mechanisms: Future Direction in Cancer

Abstract

Adducin (ADD) is a family of membrane skeleton proteins including ADD1, ADD2, and ADD3 that are encoded by distinct genes on different chromosomes. Adducin is primarily responsible for the assembly of spectrin-actin network that provides physical support to the plasma membrane and mediates signal transduction in various cellular physiological processes upon regulation by protein kinase C-dependent and calcium/calmodulin-dependent pathways. Abnormal phosphorylation, genetic variations, and alternative splicing of adducin may contribute to alterations in cellular functions involved in pathogenic processes. These alterations are associated with a wide range of diseases including cancer. This paper begins with a discussion on how adducin partakes in the structural formation of membrane skeleton, its regulation, and related functional characteristics, followed by a review on the pathogenesis of hypertension, biliary atresia, and cancer with respect to increased disease susceptibility mediated by adducin polymorphism and/or dysregulation. Given the functional diversity of adducin in different cellular compartments, we aim to provide a knowledge base whereby its pathophysiological roles can be better understood. More importantly, we aim to provide novel insights that may be of significance in turning the adducin model to clinical application.

Neocortical Expansion Due to Increased Proliferation of Basal Progenitors Is Linked to Changes in Their Morphology

“…Remarkably, this reduction was recapitulated upon KO of ADD3. Adducins are known to function in anchoring the actin cytoskeleton to the PM (Kiang and Leung, 2018). Hence, our findings strongly suggest that the observed increase in BP processes involves a PALMD-CaaX-modulated, adducinmediated interaction of the actin cytoskeleton with the PM (Figure 7J).…”

“…We next sought to obtain mechanistic insight into how PALMD-CaaX elicits the increase in BP process number. Immunoprecipitation (IP) of PALMD under stringent conditions from hNcx tissue followed by mass spectrometry (MS) ( Figure 6A; Table S2) revealed that PALMD specifically interacts with proteins that anchor the actin cytoskeleton to the PM, in particular adducins (Kiang and Leung, 2018). Among the adducins, only Add3 (adducin-g) shows an mRNA expression pattern in mNcx and hNcx that resembles that of Palmd mRNA (see Figure S6E for details, and compare to Figure S3A).…”

“…Third, a KO of ADD3 in hNcx tissue reduced the level of cycling BPs, in a very similar manner as KO of PALMD. Adducins link the actin cytoskeleton to the PM, and their involvement in cell proliferation is thought to occur indirectly via this cytoskeletal role (Kiang and Leung, 2018). Hence, the PALMD KO and the ADD3 KO phenotypes are most easily reconciled with one another by the concept that the reduction in BP process number constitutes primary effects of both KOs, reflecting the lack of the normally occurring concerted action of PALMD and ADD3 at the PM ( Figure 7J).…”

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

“…ADD3 codifies the γ-adducin, which build heterotetramers with its counterparts αand β-adducin, and has been widely studied in red-cell membranes [42]. Different works put a spotlight on adducin's controversial role as either oncogene or tumor suppressor in cancer [42][43][44][45]. Our findings support a recent report of Kiang KM et al that points to the downregulation of ADD3 in GB, but not in less malignant gliomas, as a critical event during malignant progression [46].…”

Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy

“…cg11220663 is associated with less expression of the ADD2 gene, also known as beta-adducin. ADD2 is involved in multiple pathogenic processes with a wide range of diseases 61. ADD2 gene variants are associated with hypertension,62 cancer61 and systemic lupus erythematosus 63…”