Disease relevance of PPL

• Two patients showed a defect of PPL in muscle, and were homozygous for the most common mutation associated with McArdle's disease, R49X in the muscle PPL gene (PYGM) [1].
• We conclude that the Q12X mutation in AMPD1 may result in a mild clinical effect; that it is frequent in the Spanish population, and therefore frequently associated with other metabolic diseases; and that the effect of the association of AMPD and PPL deficiencies seems to be neutral [1].
• Envoplakin and periplakin are the paraneoplastic pemphigus antigens [2].
• CONCLUSION: The association with a lymphoproliferative disorder, the IIF labeling of rat bladder, and the immunoblotting recognition of envoplakin and/or periplakin are both sensitive and specific features in the diagnosis of PNP [3].
• These results suggest that periplakin could be a useful marker for detection of early esophageal cancer and evaluation of tumor progression [4].

High impact information on PPL

• We conclude that kazrin is a novel component of desmosomes that associates with periplakin [5].
• Kazrin, a novel periplakin-interacting protein associated with desmosomes and the keratinocyte plasma membrane [5].
• Kazrin is expressed in all layers of stratified squamous epithelia; it becomes membrane associated in the suprabasal layers, coincident with up-regulation of periplakin, and is incorporated into the cornified envelope of cultured keratinocytes [5].
• Full-length periplakin localized to desmosomes, the interdesmosomal plasma membrane and intermediate filaments [6].
• The envoplakin rod domain was required for aggregation and the periplakin rod domain was necessary and sufficient to redistribute envoplakin to desmosomes and the cytoskeleton, confirming earlier predictions that the proteins can heterodimerize [6].

Chemical compound and disease context of PPL

• The members of the plakin family of proteins recognized by paraneoplastic pemphigus antibodies include periplakin [7].
• PURPOSE: This study aimed to evaluate the activity and toxicity of carboplatin (PPL) and ifosfamide (IFO) in patients with epithelial ovarian cancer previously treated with cisplatin (CDDP)-containing regimens [8].
• A depression of skin hypersensitivity to PPL and/or penicillin and penicillin derivatives sometimes persisting for weeks and months was obvious in numerous allergic patients submitted to combined Ro 6-0787-penicillin treatment [9].

Biological context of PPL

• Interspecific backcross mapping was used to place the murine periplakin gene (Ppl) 0.53 cM distal to marker D16mit32 on the proximal part of murine chromosome 16, close to the locus of mahoganoid (md), a mouse hair mutant [10].
• Mapping of this gene in human and mouse will allow evaluation of periplakin as a candidate locus for disorders of epithelial fragility, with or without other phenotypes [10].
• By expressing C-terminal PPL in transfectants, we established a pivotal role for this protein in FcgammaRI ligand binding, endocytosis, and antigen presentation [11].
• Periplakin is the first protein described to modify the capacity of the melanin-concentrating hormone-1 receptor to initiate signal transduction [12].
• By transient transfection of COS7 cells and primary human epidermal keratinocytes with deletion mutants of the periplakin C-terminus we mapped sequences required for intermediate filament interaction to two regions of the linker motif that are most highly conserved amongst the plakins [13].

Anatomical context of PPL

• Endogenous periplakin was redistributed from microvilli when keratinocytes were treated with the actin disrupting drug Latrunculin B [6].
• Unique role for the periplakin tail in intermediate filament association: specific binding to keratin 8 and vimentin [14].
• Envoplakin and periplakin are components of the cornified envelope, but less is known about their role in tissues other than the stratified epithelium [14].
• Immunohistochemistry demonstrated coexpression of periplakin with melanin-concentrating hormone-1 receptor in specific cells of the piriform cortex, amygdala, and other structures of the adult mouse brain [12].
• Both periplakin and envoplakin/periplakin oligomers were able to bind synthetic lipid vesicles whose composition mimicked the cytoplasmic side of the plasma membrane of eukaryotic cells [15].

Associations of PPL with chemical compounds

• Periplakin, a novel component of cornified envelopes and desmosomes that belongs to the plakin family and forms complexes with envoplakin [16].
• Like the NH(2) terminus of desmoplakin, that of periplakin localized to desmosomes; however, in addition, the periplakin NH(2) terminus accumulated at cell surface microvilli in association with cortical actin [6].
• Coexpression of the melanin-concentrating hormone-1 receptor with periplakin in human embryonic kidney 293 cells did not prevent agonist-mediated internalization of the receptor but did interfere with binding of (35)S-labeled guanosine 5'-3-O-(thio)triphosphate ([(35)S]GTPgammaS) to the G protein Galpha(o1) and the elevation of [Ca(2+)](i) [12].
• These findings raise the possibility that envoplakin and periplakin bind to the plasma membrane upon elevation of intracellular [Ca(2+)] in differentiating keratinocytes, where they serve as a scaffold for cornified cell envelope assembly [15].
• Biphasic cerebral uptake of tyrosine was observed during and immediately after PBZ and PPL infusion [17].

Physical interactions of PPL

• Analysis of interactions between the C-terminal tail of the MOP-1 and MOP-1A variants of the human mu-opioid receptor with proteins derived from a human brain cDNA library resulted in identification of the actin and intermediate filament-binding protein periplakin [18].
• Interactions between G-protein-coupled receptors and periplakin: a selective means to regulate G-protein activation [19].

Other interactions of PPL

• Here we demonstrate, through the use of yeast two-hybrid assay, a specific interaction of the periplakin linker domain with keratin 8 and vimentin [14].
• Closer examination in vitro revealed that while caspases 2 and 4 most efficiently cleaved DP, and plectin served as a target for caspases 3 and 7, periplakin as well as keratins were cleaved by caspase 6 [20].
• Direct interaction between FcgammaRI (CD64) and periplakin controls receptor endocytosis and ligand binding capacity [11].
• We have identified through yeast two-hybrid screening a novel protein, periphilin, interacting with periplakin, which is known as a precursor of the cornified cell envelope [21].
• PPL and FcgammaRI colocalized at the plasma membrane in monocytes and cell transfectants, and both were up-regulated by IFN-gamma [11].

Analytical, diagnostic and therapeutic context of PPL

• The human gene (PPL) was mapped to the interval between D16S510 and D16S509 by radiation hybrid mapping, corresponding to chromosomal band 16p13 [10].
• Electron microscopy of rotary-shadowed periplakin demonstrated thin flexible molecules with an average contour length of 88 nm for the rod-plus-tail fragment, and immunolabeling EM confirmed the molecule as a parallel, in-register, dimer [15].
• Using immunoblotting and immunoprecipitation, we further showed that the 190 kDa PNP antigen is identical to periplakin, another recently identified envelope precursor that can form complexes with envoplakin [2].
• RESULTS: One clinical and 2 biologic features had both high sensitivity (82%-86%) and high specificity (83%-100%) whatever the control group considered: (1) association with a lymphoproliferative disorder, (2) indirect immunofluorescence (IIF) labeling of rat bladder, and (3) recognition of the envoplakin and/or periplakin bands in immunoblotting [3].
• This was later confirmed by the presence of antibodies against envoplakin (210 kDa), periplakin (190 kDa), and desmoglein 1 on immunoprecipitation studies [22].

References