The Critical Role of the Shroom Family Proteins in Morphogenesis, Organogenesis and Disease

Abstract

The Shroom (Shrm) family of actin-binding proteins has a unique and highly conserved Apx/Shrm Domain 2 (ASD2) motif. Shroom protein directs the subcellular localization of Rho-associated kinase (ROCK), which remodels the actomyosin cytoskeleton and changes cellular morphology via its ability to phosphorylate and activate non-muscle myosin II. Therefore, the Shrm-ROCK complex is critical for the cellular shape and the development of many tissues, including the neural tube, eye, intestines, heart, and vasculature system. Importantly, the structure and expression of Shrm proteins are also associated with neural tube defects, chronic kidney disease, metastasis of carcinoma, and X-link mental retardation. Therefore, a better understanding of Shrm-mediated signaling transduction pathways is essential for the development of new therapeutic strategies to minimize damage resulting in abnormal Shrm proteins. This paper provides a comprehensive overview of the various Shrm proteins and their roles in morphogenesis and disease.

Keywords: Actin-binding proteins; Neural tube closure; Shroom; Tissue morphogenesis.

Fig. 1

Classification and Domain Architecture of Murine Shroom family. The PDZ is a domain shared by shrm2, shrm3 and shrm4 with completely different functions. The ASD1 is required for Shrm1, Shrm2, and Shrm3 to bind actin for the regulation of subcellular localization. The Apx/Shrm Domain2 (ASD2) is the signature sequence element that defines all Shrm-like proteins

Fig. 2

Regulated Mechanism of shroom3 in apical contraction. The ASD1 is required for apical localization of F-actin and the ASD2 is critical for myosin II activation via Rho-associated kinase (ROCK) recruitment that jointly contributes to apical constriction, while the PDZ is dispensable for apical constriction

Fig. 3

Functions of the shroom3 in endothelial cells. a Shroom3 is required for the apical localization of F-actin and myosin II via ASD1 and ASD2 motifs, respectively, thus contributing to apical constriction. b Shrm3 can induce apicobasal elongation by controlling γ-tubulin distribution and microtube architecture during epithelial cell shape change that is independent of apical constriction. c Shroom3 is critical for epithelial cells change during neural tube closure

Fig. 4

Molecules that influence the expression and activity Shrm3 in lens pit cell apical constriction. During the invagination process of the lens pit, p120-catenin plays a crucial role in recruiting Shrm3 to the zonula adherens. Besides, the expression and apical localization of Shrm3 are regulated by Pax6 and Trio-RhoA pathway, ultimately leading to activation of the contractile actin-myosin network and a reduction of the apical cell circumference

Fig. 5

The expression and activity of Shrm3 are regulated by Pixt1 and Pixt2-N-cadherin pathway during gut morphogenesis. In the developing gut, Pitx proteins directly activate the transcription of Shrm3 and subsequently facilitate Shrm3-dependent cytoskeletal reorganization and epithelial cell shape alteration. On the other hand, Shrm3 and a Pitx2-N-cadherin pathway function cooperatively to generate asymmetric cell shape changes during gut morphogenesis

Fig. 6

Shroom3 facilitates canonical TGF-β1/Smad3 signaling and profibrotic gene expression. The rs17319721 allele at the Shroom3 is a transcription factor 7- like 2- dependent (TCF7L2-dependent) enhancer element that functions to increase Shroom3 transcription. In renal tubular cells, TGF-β1 administration upregulated expression Shroom3 in a β-catenin/TCF7L2-mediated manner, while Shroom3 in turn facilitated canonical TGF-β1 signaling and increased α1 collagen (COL1A1) expression thus contribute to allograft fibrosis