Myelin basic protein: a multifunctional protein

Myelin basic protein (MBP), the second most abundant protein in central nervous system myelin, is responsible for adhesion of the cytosolic surfaces of multilayered compact myelin. A member of the ‘intrinsically disordered’ or conformationally adaptable protein family, it also appears to have several other functions. It can interact with a number of polyanionic proteins including actin, tubulin, Ca²⁺-calmodulin, and clathrin, and negatively charged lipids, and acquires structure on binding to them. It may act as a membrane actin-binding protein, which might allow it to participate in transmission of extracellular signals to the cytoskeleton in oligodendrocytes and tight junctions in myelin. Some size isoforms of MBP are transported into the nucleus and thus they may also bind polynucleotides. Extracellular signals received by myelin or cultured oligodendrocytes cause changes in phosphorylation of MBP, suggesting that MBP is also involved in signaling. Further study of this very abundant protein will reveal how it is utilized by the oligodendrocyte and myelin for different purposes. Received 2 March 2006; received after revision 12 April 2006; accepted 16 May 2006     

Apical protein transport

The plasma membrane of epithelial cells and hepatocytes is divided into two separate membrane compartments, the apical and the basolateral domain. This polarity is maintained by intracellular machinery that directs newly synthesized material into the correct target membrane. Apical protein sorting and trafficking require specific signals and different intracellular routes to the cell surface. Some of them depend on the integrity of sphingolipid/cholesterol-enriched membrane microdomains named ‘lipid rafts’, others use separate transport platforms. Certain characteristics of the heterogeneous population of apical sorting signals are described in this review and cellular factors associated with sorting and transport mechanisms are discussed. Received 5 May 2006; received after revision 12 June 2006; accepted 11 July 2006     

Cathepsin A/protective protein: an unusual lysosomal multifunctional protein

Cathepsin A/protective protein [3.4.16.5], carboxypeptidase A, is a lysosomal serine protease with structural homology to yeast (Saccharomyces cerevisiae) carboxypeptidase Y. Cathepsin A is a member of the alpha/beta hydrolase fold family and has been suggested to share a common ancestral relationship with other alpha/beta hydrolase fold enzymes, such as cholinesterases. Several lines of evidence indicate that cathepsin A is a multicatalytic enzyme with deamidase and esterase in addition to carboxypeptidase activities. Cathepsin A was recently identified in human platelets as deamidase. In vitro, it hydrolyzes a variety of bioactive peptide hormones including tachykinins, suggesting that extralysosomal cathepsin A plays a role in regulation of bioactive peptide functions. Recent reports emphasize the lysosomal protective function of cathepsin A rather than its protease function. The protective function of cathepsin A is distinct from its catalytic function. Human lysosomal beta-galactosidase and neuraminidase exist as a high molecular weight enzyme complex, in which there is a 54-kDa glycoprotein termed 'lysosomal protective protein'. Based on cell culture studies, protective protein was found to protect both beta-galactosidase and neuraminidase from intralysosomal proteolysis by forming a multienzyme complex and was shown to be deficient in patients with galactosialidosis, a combined deficiency of beta-galactosidase and neuraminidase. Molecular cloning and gene expression studies have disclosed that protective protein is cathepsin A. The cathepsin A precursor has the potential to restore both beta-galactosidase and neuraminidase activities in fibroblasts from patients with galactosialidosis. Cathepsin A knockout mice showed a phenotype similar to human galactosialidosis and the deficient phenotype found in the mutant mice was corrected by transplanting erythroid precursor cells overexpressing cathepsin A. Collectively, these findings demonstrate the significance of cathepsin A as a key molecule in the onset of galactosialidosis and also highlight the therapeutic potential of the cathepsin A precursor for patients with galactosialidosis.     

Coronavirus envelope protein: A small membrane protein with multiple functions

Coronavirus envelope protein is a small membrane protein and minor component of the virus particles. It plays important roles in virion assembly and morphogenesis, alteration of the membrane permeability of host cells and virus-host cell interaction. Here we review recent progress in characterization of the biochemical properties, membrane topology and functions of the protein. Received 27 February 2007; received after revision 4 April 2007; accepted 26 April 2007     

An attempt to transfer tumor protein specificity to a foreign protein

Résumé L'essai de transférer la spécificité des protéines d'une tumeur à une protéine étrangère par un procédé sérologique, a donné un résultat négatif.     

A rhodopsin-like protein in Cyanophora paradoxa: gene sequence and protein immunolocalization

Here, we report the DNA sequence of the rhodopsin gene in the alga Cyanophora paradoxa (Glaucophyta). The primers were designed according to the conserved regions of prokaryotic and eukaryotic rhodopsin-like proteins deposited in the GenBank. The sequence consists of 1,272 bp comprised of 5 introns. The correspondent protein, named Cyanophopsin, showed high identity to rhodopsin-like proteins of Archea, Bacteria, Fungi, and Algae. At the N-terminal, the protein is characterized by a region with no transmembrane α-helices (80 aa), followed by a region with 7α-helices (219 aa) and a shorter 35-aa C-terminal region. The DNA sequence of the N-terminal region was expressed in E. coli and the recombinant purified peptide was used as antigen in hens to obtain polyclonal antibodies. Indirect immunofluorescence in C. paradoxa cells showed a marked labeling of the muroplast (aka cyanelle) membrane.     

CAP2, cyclase-associated protein 2, is a dual compartment protein

Cyclase-associated proteins (CAPs) are evolutionarily conserved proteins with roles in regulating the actin cytoskeleton and in signal transduction. Mammals have two CAP genes encoding the related CAP1 and CAP2. We studied the distribution and subcellular localization of CAP1 and CAP2 using specific antibodies. CAP1 shows a broad tissue distribution, whereas CAP2 is significantly expressed only in brain, heart and skeletal muscle, and skin. CAP2 is found in the nucleus in undifferentiated myoblasts and at the M-line of differentiated myotubes. In PAM212, a mouse keratinocyte cell line, CAP2 is enriched in the nucleus, and sparse in the cytosol. By contrast, CAP1 localizes to the cytoplasm in PAM212 cells. In human skin, CAP2 is present in all living layers of the epidermis localizing to the nuclei and the cell periphery. In in vitro studies, a C-terminal fragment of CAP2 interacts with actin, indicating that CAP2 has the capacity to bind to actin.     

Oncogenic protein tyrosine kinases

Signals through Kit receptor tyrosine kinase are essential for development of erythrocytes, melanocytes, germ cells, mast cells and interstitial cells of Cajal (ICCs). Mice and rats with a double gene dose of loss-of-function mutations of Kit show depletion of these cells. Although human homozygotes with loss-of-function mutations of Kit have not been reported, gain-of-function mutations of Kit result in development of tumors from mast cells, germ cells and ICCs in humans. The ICC tumors are called gastrointestinal stromal tumors (GISTs), and GISTs are a good target for the Kit inhibitor imatinib mesylate. The interrelationship between the type of Kit gain-of-function mutations and the therapeutic effect of imatinib mesylate has been well characterized in GISTs. Kit is interesting from both a biological and clinical view-point.     

Oncogenic protein tyrosine kinases

HER2 (human epidermal growth factor receptor-2; also known as erbB2) and its relatives HER1 (epidermal growth factor receptor; EGFR), HER3 and HER4 belong to the HER family of receptor tyrosine kinases. In normal cells, activation of this receptor tyrosine kinase family triggers a rich network of signaling pathways that control normal cell growth, differentiation, motility and adhesion in several cell lineages. The first tumor studied for an alteration of the HER2 oncogene is breast carcinoma, and so far the majority of studies have been performed on this oncotype. Although involvement of HER2 as a cause of human cell transformation needs to be further investigated, overexpression of the HER2 oncogene in human breast carcinomas has been associated with a more aggressive course of disease. It has been suggested that this association depends on HER2-driven proliferation, vessel formation and/or invasiveness; however, poor prognosis may not be directly related to the presence of the oncoprotein on the cell membrane but instead to the breast carcinoma subset identified by HER2 overexpression and characterized by a peculiar gene expression profile, as recently identified. HER2-positive tumors were recently shown to benefit from anthracyclin treatment and to be resistant to endocrine therapy. Despite the fact that many pathways interacting with HER2 are still not fully understood, this tyrosine kinase receptor is, to date, a promising molecule for targeted therapy.     

Oncogenic protein tyrosine kinases

RET is the receptor for glial-derived neurotrophic factor growth factors. It is a paradigm of a single gene that causes different types of human cancer when targeted by different genetic alterations. Like other receptor tyrosine kinases, once activated, RET recruits a variety of signaling molecules that mediate biological responses. Here we review data on the signaling pathways that lead to RET-mediated cell transformation and recent evidence that manipulation of RET holds promise for thyroid cancer treatment.     

Oncogenic protein tyrosine kinases

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, the normal role of which remains to be completely elucidated. Although work carried out in mammals suggests a function in neural development, results from studies in Drosophila indicate an additional role in visceral muscle differentiation. The aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas, while the occurrence of ALK fusion proteins in anaplastic large cell lymphoma (ALCL) has resulted in the identification of the new tumor entity, ALK-positive ALCL. ALK represents one of few examples of a receptor tyrosine kinase implicated in oncogenesis in both haematopoietic and non-haematopoietic tumors, given that ALK fusions also occur in the mesenchymal tumor known as inflammatory myofibroblastic tumor (IMT). The study of ALK fusion proteins, besides demonstrating their importance in tumor development, has also raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies.     

Oncogenic protein tyrosine kinases

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Oncogenic protein tyrosine kinases

Since it was first recognized, chronic myeloid leukemia (CML) has always represented a unique model to understand the molecular mechanisms underlying the onset and progression of a leukemic process. CML was the first recognized form of cancer to have a strong association with a recurrent chromosomal abnormality, the t(9;22) translocation, which generates the so-called Philadelphia (Ph)-chromosome. Twenty years later, this abnormality was shown to cover a specific molecular defect, a hybrid BCR-ABL gene, strongly implicated in the pathogenesis of the disease through the production of a protein with a constitutive tyrosine-kinase activity. Although we still lack a complete definition of all the transformation pathways activated by Bcr-Abl, the recent introduction into clinical practice of tyrosine kinase inhibitor represents a major breakthrough to the management of CML and, furthermore, promises to usher in molecularly targeted therapy for other types of leukemia, lymphoma and cancer.     

Oncogenic protein tyrosine kinases

FLT3, a member of the class III receptor tyrosine kinases (RTKs), is preferentially expressed on the cell surface of hematopoietic progenitors, and the ligand of FLT3 (FL) is expressed as a membrane-bound or soluble form by bone marrow stroma cells. It has been disclosed that FL-FLT3 interaction plays an important role in the maintenance, proliferation and differentiation of hematopoiesis. FLT3 is also expressed in a high proportion of acute myeloid leukemia (AML) and B-lineage acute lymphoblastic leukemia cells. Activating mutations of FLT3 are the most frequent genetic lesions in AML, and AML patients with FLT3 mutations have a worse prognosis than those with normal FLT3. Exploring the mechanism by which FLT3 mutations cause autoactivation and uncontrolled signaling might lead to a better understanding of how FLT3 becomes oncogenic and provide insights for the development of new drugs.     

Oncogenic protein tyrosine kinases

Platelet-derived growth factor receptors (PDGFRs) and their ligands, platelet-derived growth factors (PDGFs) play critical roles in mesenchymal cell migration and proliferation. In embryogenesis the PDGFR/PDGF system is essential for the correct development of the kidney, cardiovascular system, brain, lung and connective tissue. In adults, PDGFR/PDGF is important in wound healing, inflammation and angiogenesis. Abnormalities of PDGFR/PDGF are thought to contribute to a number of human diseases, and especially malignancy. Constitutive activation of the PDGFRalpha or PDGFRbeta receptor tyrosine kinases is seen in myeloid malignancies as a consequence of fusion to diverse partner genes, and activating mutations of PDGFRalpha are seen in gastrointestinal tumours (GISTs). Autocrine signalling as a consequence of PDGF-B overexpression is clearly implicated in the pathogenesis of dermatofibrosarcoma protruberans (DFSP) and overexpression of PDGFRs and/or their ligands has been described in many solid tumours. PDGFR signalling is inhibited by imatinib mesylate, and this compound has clear clinical activity in patients with myeloid malignancies, GIST and DFSP.     

The role of survival motor neuron protein (SMN) in protein homeostasis

Ever since loss of survival motor neuron (SMN) protein was identified as the direct cause of the childhood inherited neurodegenerative disorder spinal muscular atrophy, significant efforts have been made to reveal the molecular functions of this ubiquitously expressed protein. Resulting research demonstrated that SMN plays important roles in multiple fundamental cellular homeostatic pathways, including a well-characterised role in the assembly of the spliceosome and biogenesis of ribonucleoproteins. More recent studies have shown that SMN is also involved in other housekeeping processes, including mRNA trafficking and local translation, cytoskeletal dynamics, endocytosis and autophagy. Moreover, SMN has been shown to influence mitochondria and bioenergetic pathways as well as regulate function of the ubiquitin–proteasome system. In this review, we summarise these diverse functions of SMN, confirming its key role in maintenance of the homeostatic environment of the cell.