The Paralemmin Protein Family: Identification of Paralemmin-2, an Isoform Differentially Spliced to AKAP2/AKAP-KL, and of Palmdelphin, a More Distant Cytosolic Relative

doi:10.1006/bbrc.2001.5329

Biochemical and Biophysical Research Communications

Volume 285, Issue 5, 3 August 2001, Pages 1369-1376

https://doi.org/10.1006/bbrc.2001.5329 Get rights and content

Abstract

Paralemmin is a protein implicated in plasma membrane dynamics. Here we describe the identification of two new paralemmin-related proteins. A partial paralemmin homolog, palmdelphin, is predominantly cytosolic, unlike paralemmin which is lipid-anchored to the plasma membrane through a C-terminal CaaX motif. We have mapped the mouse palmdelphin gene to distal chromosome 3 between Amy2 and Abcd3, in a region homologous to human chromosome 1p22-p21 where the human palmdelphin gene is located. We have also identified a second paralemmin isoform, paralemmin-2. It is expressed from a gene on human chromosome 9q31-q33 which ends only 33 kb upstream of the gene encoding the protein kinase A-binding protein,AKAP2/AKAP-KL. The closely adjacent paralemmin-2 and AKAP2 genes are functionally linked in a very unusual manner. Chimeric mRNAs are expressed, apparently by RNA readthrough and differential splicing, that encode natural fusion proteins in which either the N-terminal coiled-coil region or nearly the complete sequence of paralemmin-2 except its C-terminal CaaX motif is fused to AKAP2/AKAP-KL. The N-terminal coiled-coil region is conserved in paralemmin-1, paralemmin-2/AKAP2, palmdelphin and a fourth, uncharacterized gene, suggesting that it is a modular functional domain.

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Neocortical Expansion Due to Increased Proliferation of Basal Progenitors Is Linked to Changes in Their Morphology
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Citation Excerpt :
This way we identified PALMDELPHIN (PALMD) (Figure 3A; Table S1; see STAR Methods for details and Figure S3A for Palmd mRNA expression), a gene whose protein product belongs to the paralemmin family of morpho-regulatory proteins. Paralemmins have been shown to be implicated in the control of cell shape, neurite growth, and filopodia extension (Arstikaitis et al., 2008; Hu et al., 2001; Kutzleb et al., 1998). Previous studies on Palm1, the founding member of this family, suggest that these functions depend on its attachment to the plasma membrane (PM) (Kutzleb et al., 1998).
The evolutionary expansion of the mammalian neocortex (Ncx) is thought to be linked to increased proliferative capacity of basal progenitors (BPs) and their neurogenic capacity. Here, by quantifying BP morphology in the developing Ncx of mouse, ferret, and human, we show that increased BP proliferative capacity is linked to an increase in BP process number. We identify human membrane-bound PALMDELPHIN (PALMD-Caax) as an underlying factor, and we show that it drives BP process growth and proliferation when expressed in developing mouse and ferret Ncx. Conversely, CRISPR/Cas9-mediated disruption of PALMD or its binding partner ADDUCIN-γ in fetal human Ncx reduces BP process numbers and proliferation. We further show that PALMD-induced processes enable BPs to receive pro-proliferative integrin-dependent signals. These findings provide a link between BP morphology and proliferation, suggesting that changes in BP morphology may have contributed to the evolutionary expansion of the Ncx.
A novel binding protein of single immunoglobulin IL-1 receptor-related molecule: Paralemmin-3
2011, Biochemical and Biophysical Research Communications
Citation Excerpt :
The paralemmin protein family includes four proteins – paralemmin-1, paralemmin-2, paralemmin-3, and palmdelphin [11]. Previous studies have demonstrated that the paralemmin protein family is implicated in the plasma membrane dynamics [14–17]. At the present, the exact role of PALM3 is still unclear.
Previous studies have shown that single immunoglobulin IL-1 receptor-related molecule (SIGIRR) is a negative regulator of Toll-Interleukin-1 receptor signaling. Nevertheless, the molecular mechanism of the negatively regulatory effect of SIGIRR remains unknown. Using a yeast two-hybrid screen, we identified paralemmin-3 (PALM3) as a novel binding protein of SIGIRR. This interaction of SIGIRR with PALM3 was confirmed by coimmunoprecipitation in mammalian cells. In addition, the PALM3 mRNA expression was upregulated by lipopolysaccharide (LPS)-stimulation in a human alveolar epithelial cell line (A549 cells). Furthermore, silencing PALM3 by RNA interference inhibited the release of inflammatory cytokines in A549 cells after LPS-stimulation. These results suggest that PALM3 may function as an adaptor in the LPS- Toll-like receptor 4 signaling and the interaction of SIGIRR with PALM3 may partly account for the mechanism of the negatively regulatory effect of SIGIRR.
Use of MicroRNA expression levels to predict outcomes in resected stage i non-small cell lung cancer
2010, Journal of Thoracic Oncology
Citation Excerpt :
Both CDKN1B and CDKN1C (p57Kip2) have been experimentally shown to be attenuated by miR-221 in various tissue types.34,35 Both PALM2, implicated in cell membrane dynamics, and CXCL12 (SDF1), a chemoattractant, are computationally predicted to be bound and regulated by miR-221.36–38 We found a near significant 2.5-fold reduction (p = 0.052) in CDKN1B expression between recurrent and nonrecurrent tumors (Figure 6); however, an evaluation of the protein level expression of CDKN1B would be necessary to confirm the significance of this finding.
Despite undergoing curative resection, nearly a third of patients with stage I non-small cell lung cancer (NSCLC) die of recurrent disease. There are no reliable clinical or molecular predictors of relapse in patients with resected stage I NSCLC. Identifying patients at risk for relapse after surgical resection is one of the important challenges today. MicroRNAs (miRNAs) regulate hundreds of genes central to maintaining a cancer phenotype.
In an exploratory study, we determined whether expression of six miRNAs (let-7a, miR-7, miR-21, miR-155, miR-210, and miR-221) previously reported to correlate with invasiveness or outcome in various human malignancies were associated with tumor recurrence in patients with resected stage I NSCLC. We measured expression of these miRNAs in formalin-fixed, paraffin-embedded tissue from both tumor and matched normal lung in a set of 46 patients with surgically resected T1 or T2 stage I NSCLC.
Averaged triplicate data showed that tumors which recurred had 0.14-fold lower miR-221 expression than those which did not recur (p = 0.0036). In addition, increased miR-221in tumor tissue when compared with adjacent normal appearing lung in the same patient also correlated with nonrecurrence (p = 0.0011). Parallel measurement of expression of selected downstream target genes regulated by miR-221, specifically, CDKN1B, CDKN1C, paralemmin-2, and CXCL12, showed a near significant (p = 0.0522) down-regulation of CDKN1C in tumors of patients with no recurrent disease, consistent with increased miR-221 activity in the same group.
If confirmed in prospective studies, miRNA expression in resected NSCLC could potentially identify those at high risk of relapse after surgery.
Identification of genes expressed in retinal progenitor/stem cell colonies isolated from the ocular ciliary body of adult mice
2006, Gene Expression Patterns
Rare pigmented cells showing retinal stem cell characteristics have been identified in the ocular ciliary body (CB) of adult mammals. In vitro, these cells were reported to clonally proliferate and generate pigmented sphere colonies (PSC) containing multipotent retinal progenitor-like cells. Because these cells may have important clinical applications and because their embryonic origin is unclear, we have analyzed their local environment and gene expression profile. We found that transcription factors Pax6, Six3, and Rx, all involved in early eye morphogenesis, were expressed in the CB of adult mice. By sequencing a PSC cDNA library, we found that PSC expressed at high levels transcripts involved in the control of redox metabolism and cellular proliferation. PSC also expressed the retinal transcription factor Six6, which expression was not detected in the CB epithelium. By in situ hybridization screen, we found that Palmdelphin (Palm), Hmga2, and a novel transcript were expressed in the central nervous system of early embryos. Palm expression delineated the pigmented epithelium of the future CB and the developing myotome. Hmga2 was expressed in the ventricular zone of the telencephalon, the developing retinal ciliary margin and lens. Several genes expressed in PSC were also expressed in the nasal anlagen. Taken together, our study reveals that PSC isolated from the ocular CB express genes involved in the control of embryonic development, retinal identity, redox metabolism, and cellular proliferation.
Read-through transcript from NM23-H1 into the neighboring NM23-H2 gene encodes a novel protein, NM23-LV
2006, Genomics
NM23-H1 and NM23-H2 are neighboring genes on chromosome 17q. They encode nucleoside diphosphate kinases that have additional roles in signal transduction, transcription, and apoptosis. NM23-H1 expression is a strong marker for prognosis and metastatic behavior in many tumor types. A new bioinformatic tool, TranscriptView, identified read-through transcripts that start in the NM23-H1 gene and continue in the neighboring NM23-H2 gene. Splicing results in a transcript containing exons 1 to 4 of NM23-H1 and exons 2 to 5 of NM23-H2. The resulting mRNA encodes a novel and long variant of the NM23 protein family, NM23-LV, which contains part of NM23-H1 and the complete NM23-H2 protein. The transcript was amplified and sequenced from two neuroblastoma cell lines, confirming the presence of the predicted NM23-LV mRNA in vivo. Tissue analysis showed that NM23-LV is ubiquitously expressed, with the exception of the kidney. Neuroblastoma tumors show high-level expression of NM23-H1 and-H2 as well as NM23-LV mRNA. In neuroblastoma cells, the NM23-LV protein has mainly a cytoplasmic localization, but some nuclear staining was observed as well.
Molecular characterization and immunohistochemical localization of palmdelphin, a cytosolic isoform of the paralemmin protein family implicated in membrane dynamics
2005, European Journal of Cell Biology
Palmdelphin is a newly identified cytosolic isoform of paralemmin-1, a lipid raft-associated protein implicated in cell shape control. Like paralemmin-1, palmdelphin is phosphorylated, giving rise to electrophoretic band heterogeneity that is most pronounced in the brain. In ultracentrifugation and gel filtration palmdelphin behaves as a non-globular monomer. Its C-terminal region binds glutamine synthetase. Immunohistochemical analysis of the rat brain shows a prominent localization of palmdelphin in the cerebral cortex, hippocampus, amygdala, septum, indusium griseum, piriform cortex, nucleus supraopticus, and nucleus of the lateral olfactory tract. Many of the circumscript palmdelphin-positive areas are related to the olfactory system. Immunoperoxidase electron microscopy reveals a discontinuous distribution of palmdelphin immunoreactivity, in the form of spots scattered throughout the cytoplasm of selected neuronal perikarya and dendrites, including dendritic spines, often in association with endomembranes, and in a pattern which is similar to that of the cytoplasmic fraction of paralemmin-1. In subcellular fractionation experiments palmdelphin behaves as a cytosolic protein which, however, can be partially recruited from cytosol to the detergent-resistant fraction of a membrane/cytoskeletal cell ghost preparation. These observations suggest that palmdelphin may peripherally associate with endomembranes or cytoskeleton-linked structures.

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Biochemical and Biophysical Research Communications

Abstract

References (9)

Development and applications of a molecular genetic linkage map of the mouse genome

Trends Genet.

Localization of the 70-kDa peroxisomal membrane protein to human 1p21-p22 and mouse 3

Genomics

Structure of the human paralemmin gene (PALM), mapping to human chromosome 19p13.3 and mouse chromosome 10, and exclusion of coding mutations in grizzled, mocha, jittery and hesitant mice

Genomics

Molecular characterization of a cDNA that encodes six isoforms of a novel A kinase anchor protein

J. Biol. Chem.

Cited by (27)

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

A novel binding protein of single immunoglobulin IL-1 receptor-related molecule: Paralemmin-3

Use of MicroRNA expression levels to predict outcomes in resected stage i non-small cell lung cancer

Identification of genes expressed in retinal progenitor/stem cell colonies isolated from the ocular ciliary body of adult mice

Read-through transcript from NM23-H1 into the neighboring NM23-H2 gene encodes a novel protein, NM23-LV

Molecular characterization and immunohistochemical localization of palmdelphin, a cytosolic isoform of the paralemmin protein family implicated in membrane dynamics

Regular ArticleThe Paralemmin Protein Family: Identification of Paralemmin-2, an Isoform Differentially Spliced to AKAP2/AKAP-KL, and of Palmdelphin, a More Distant Cytosolic Relative

Abstract

Trends Genet.

Genomics

Genomics

J. Biol. Chem.

Regular Article
The Paralemmin Protein Family: Identification of Paralemmin-2, an Isoform Differentially Spliced to AKAP2/AKAP-KL, and of Palmdelphin, a More Distant Cytosolic Relative