Dr. Sandra Iden
Cell polarization is crucial for the development of multicellular organisms and aberrant cell polarization contributes to various diseases. Seminal studies in invertebrates identified proteins that regulate various polarization processes including asymmetric cell division and epithelial cell polarization. Polarity proteins may react to extrinsic polarity cues such as growth factor gradients or extrinsic cues such as the microtubule cytoskeleton. By assembling multiprotein complexes, they induce downstream signaling to establish cellular asymmetry. Of the three polarity protein complexes described so far – Par3, Crumbs and Scribble – the Par3 complex has the broadest function. Furthermore, cross-talk between polarity proteins and Rho GTPase signaling components controls formation of cell-cell contacts and apico-basal polarity in epithelial cells. For decades, loss of apico-basal polarity has been considered a prerequisite for tumor formation and progression.
The research of our junior group focuses on the function of polarity proteins in skin homeostasis and in age-related pathologic conditions including cancer. We are investigating cell type-specific functions of polarity proteins, and studying the consequences of deregulated polarity signaling on cellular architecture, survival mechanisms and cell death. Overall, our aim is to gain a better understanding of aging-associated skin pathologies, which may reveal future directions for targeted therapies.
Figures
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Figure 1: Polarity proteins of the Par3, Crumbs and Scribble complexes. Three conserved protein complexes — the partitioning defective (Par), Crumbs and Scribble complexes — control many polarization processes in different organisms. The polarity proteins were initially studied in Drosophila melanogaster and Caenorhabditis elegans, but all of them have at least one homolog in mammals.The par genes were first identified in C.elegans. Two of these genes encode the PDZ-domain proteins Par3 and Par6 which, together with the Ser/Thr kinase atypical protein kinase C (aPKC), constitute the Par complex. Isoforms of Par3, Par6 and aPKC are ubiquitously expressed and are involved in various cell polarization processes. The kinase activity of aPKC is required for a functional Par complex, and aPKC-mediated phosphorylation of target proteins is a key event of downstream polarity signaling. The Crumbs complex comprises the transmembrane protein Crumbs and the cytoplasmic scaffolding molecules PALS1 and PATJ. A genetic interaction of the cytoplasmic proteins Scribble, Discs large (Dlg) and Lethal giant larvae (Lgl) was first described in D. melanogaster. In polarized mammalian epithelial cells, the Par3 and Crumbs-3 complexes localize predominantly to TJs, whereas components of the Scribble complex show basolateral localization. Several molecular interactions between the three complexes have been identified. Mutual exclusion of the Scribble complex and the apical junctional complexes controls apico–basal polarity, and aPKC-mediated phosphorylation of Lgl2 and Par1, another conserved polarity protein (not shown) maintains the asymmetric distribution of polarity regulators. AJ, adherens junction, TJ, tight junction. (adapted from Iden & Collard, NRMCB 2008).
Figure 2: Crosstalk between Rho GTPases and polarity proteins during the formation of epithelial apico–basal cell polarity. Simplified schematic of apico–basal polarization. Following epithelial (E)‑cadherin clustering, structural proteins (those that form AJs and TJs) and signalling proteins, including α‑catenin, β‑catenin, afadin and ZO-1, are recruited to immature cell–cell contacts. Transmembrane proteins of the junctional adhesion molecule (JAM) and nectin family are implicated in localizing the Par complex to primordial adhesions. Rho GTPases are activated downstream of cadherin clustering by unknown mechanisms. Through association with Par3, T‑cell‑lymphoma invasion and metastasis‑1 (Tiam1) couples E‑cadherin-dependent Rac1 activation to activation of aPKC, thereby inducing phosphorylation of downstream targets and subsequent polarization and maturation into fully polarized epithelium. (adapted from Iden & Collard, NRMCB 2008).
Figure 3: Mechanisms inducing loss of epithelial polarity and EMT. a Transforming growth factor‑β (TGFβ) induces epithelial–mesenchymal transition (EMT) through different mechanisms, including targeting of polarity proteins and Rho GTPases. b Ligand‑activated TGFβ receptor II (TGFβRII) phosphorylates Par6, which in turn activates the E3 ubiquitin ligase Smurf1 and thereby induces proteasomal degradation of RhoA, loss of the actomyosin ring and breakdown of apico–basal polarity. c TGFβ also induces transcriptional downregulation of Par3, resulting in the cytoplasmic localization of aPKC and Par6, downregulation of E‑cadherin and loss of TJs and AJs. d Furthermore, TGFβ activates the transcriptional repressor Snail, which inhibits Crumbs-3 expression, leading to the relocalization of the Crumbs-3 complex proteins PALS1 and PATJ as well as of the Par complex, followed by loss of apico–basal polarity. Another early event during EMT is the loss of basally localized RhoA activity, which results in the disassembly of basal microtubules, disruption of integrin‑mediated adhesion and the subsequent breakdown of the basement membrane. (adapted from Iden & Collard, NRMCB 2008).
