Nucleocytoplasmic functions of the PDZ‐LIM protein family: new insights into organ development

Abstract

Recent work on the PDZ-LIM protein family has revealed that it has important activities at the cellular level, mediating signals between the nucleus and the cytoskeleton, with significant impact on organ development. We review and integrate current knowledge about the PDZ-LIM protein family and propose a new functional role, sequestering nuclear factors in the cytoplasm. Characterized by their PDZ and LIM domains, the PDZ-LIM family is comprised of evolutionarily conserved proteins found throughout the animal kingdom, from worms to humans. Combining two functional domains in one protein, PDZ-LIM proteins have wide-ranging and multi-compartmental cell functions during development and homeostasis. In contrast, misregulation can lead to cancer formation and progression. New emerging roles include interactions with integrins, T-box transcription factors, and receptor tyrosine kinases. Facilitating the assembly of protein complexes, PDZ-LIM proteins can act as signal modulators, influence actin dynamics, regulate cell architecture, and control gene transcription.Keywords: actin cytoskeleton; organogenesis; PDZ-LIM; scaffold; T-box Evolutionarily conserved building blocks for a heterogeneous protein familyThe PDZ-LIM family is comprised of proteins with multiple functional domains, and all share a PDZ domain combined with at least one LIM domain. As protein-protein interaction modules, PDZ and LIM domains act as scaffolds, binding to filamentous actin-associated proteins, a range of cytoplasmic signaling molecules, and nuclear proteins, allowing this family to carry out diverse functions during development and adulthood.( Figure 1 shows the architecture of the PDZ-LIM protein subfamilies and their phylogenetic relationship. While both the PDZ and the LIM domains are often found in combination with other peptide motifs or domains, the coevolution of the two invariant functional domains, PDZ and LIM, indicate high functional relevance and, thus, is of particular interest and the focus of this review. All family members associate with the actin cytoskeleton, and this property, organizing protein complexes at the cytoskeleton, may serve a range of unexpected, yet important biological roles. PDZ domainFound in bacteria, yeast, and throughout the animal kingdom, the PDZ domain is one of the most common protein-protein binding domains. (17,19) It is characterized by a highly conserved sequence of 80-90 amino acids consisting of

Lysine Methylation of Progesterone Receptor at Activation Function 1 Regulates both Ligand-independent Activity and Ligand Sensitivity of the Receptor

“…In addition to regulating collagen fibrillogenesis, LUM has been reported to inhibit cell migration in melanoma cells and human mesenchymal stem cells via integrin ␤1 (64,65). PDLIM1/Elfin binds to filamentous actin-associated proteins and regulates organ development (66,67). In agreement with its heightened activity on cell spreading, PRB-K464Q mediated greater induction of LUM and PDLIM1 by R5020 as compared with WT PRB (Fig.…”

Loss of MicroRNA-17∼92 in Smooth Muscle Cells Attenuates Experimental Pulmonary Hypertension via Induction of PDZ and LIM Domain 5

“…PDLIM5 acts as an adaptor protein to Relative units sequester transcription factors in the cytoplasm or interacts with kinases to exert its effects (57,(59)(60)(61)(62). Consistent with decreased miR-17z92 in APAH PASMC, PDLIM5 is up-regulated in APAH but not in IPAH PASMC ( Figure 6; Figure E11).…”

“…In an attempt to identify the mechanism underlying the positive regulation of TGF-b 3 /Smad3 by miR17z92 in PASMC, we found that miR-17/ 20a directly suppressed PDLIM5 (Figure 4; Figures E4 and E5), a member of the PDZ-LIM protein family, that acts as a signal modulator to influence organ development and different disease states (57,58). PDLIM5 acts as an adaptor protein to Relative units sequester transcription factors in the cytoplasm or interacts with kinases to exert its effects (57,(59)(60)(61)(62).…”

“…Because ID family proteins are well implicated in BMP signaling and PAH (66,67), it will be of interest to investigate whether PDLIM5 regulates Smad nuclear/cytosol in an ID-dependent pathway. Alternatively, PDLIM5 may regulate Smad phosphorylation by protein kinase C, as PDLIM5 also recruit activated protein kinase C and its substrates to promote phosphorylation (57,61,62). Further studies are needed to address these possibilities.…”

Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice

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