Tissue survey of mammalian modulator-dependent protein kinases

Summary The levels of modulator-dependent protein kinases and protamine-dependent protein kinase(s) in various tissues of adult mice were compared. Cerebellum contained the highest levels of both modulator-dependent protein kinases and protamine-dependent protein kinase(s), whereas skeletal muscle contained no detectable enzymes. The lung and the ileum were also rich in modulator-dependent protein kinases, while other tissues were poor sources of these enzymes.Acknowledgments. This work was supported by grants (RR-08119-PK project from the National Institutes of Health, USA. and CDP-8004200 from the National Science Foundation, USA.     

Separation of modulator-dependent protein kinase (type I) from cyclic GMP-dependent protein kinase in mouse testes

A new type of enzyme, modulator-dependent protein kinase (type I) (M-PKI), was successfully isolated from the cytosol fraction of mouse testes. It was eluted slightly after the peak of cyclic GMP-dependent protein kinase (G-PK) by Sephadex G-200 gel filtration. Unlike either cyclic AMP-dependent protein Kinase (A-PK) or G-PK, its maximal activity depended exclusively on the presence of crude protein kinase modulators (PKM) or partially purified stimulatory modulator (PKMs).     

Conversion of mammalian cyclic GMP-dependent protein kinase into modulator-dependent protein kinase (type II) in vitro

The spontaneous conversion of mammalian cyclic GMP-dependent protein kinase (G-PK) into modulator-dependent protein kinase (type II) (M-PKII) in the absence of cGMP or histone was observed in vitro. The findings, together with similarity in substrate protein specificity, suggest that M-PKII is the catalytic subunit of mammalian G-PK.     

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

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

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

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.     

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.     

Structural biology of protein tyrosine kinases

Our current understanding of the structure, mechanism of action and modes of regulation of the protein tyrosine kinase family owes a great deal to structural biology. Structures are now available for more than 20 different tyrosine kinase domains, many of these in multiple conformational states. They form the basis for the design of experiments to further investigate the role of different structural elements in the normal function and regulation of the protein and in the pathogenesis of many human diseases. Once thought to be too similar to be specifically inhibited by a small molecule, structural differences between kinases allow the design of compounds which inhibit only an acceptable few. This review gives a general overview of protein tyrosine kinase structural biology, including a discussion of the strengths and limitations of the investigative methods involved. Received 2 May 2006; received after revision 21 June 2006; accepted 9 August 2006     

Osmotic stress signaling via protein kinases

Plants face various kinds of environmental stresses, including drought, salinity, and low temperature, which cause osmotic stress. An understanding of the plant signaling pathways that respond to osmotic stress is important for both basic biology and agriculture. In this review, we summarize recent investigations concerning the SNF1-related protein kinase (SnRK) 2 kinase family, which play central roles in osmotic stress responses. SnRK2s are activated by osmotic stress, and a mutant lacking SnRK2s is hypersensitive to osmotic stress. Many questions remain about the signaling pathway upstream and downstream of SnRK2s. Because some SnRK2s also functions in the abscisic acid (ABA) signaling pathway, which has recently been well clarified, study of SnRK2s in ABA signaling can provide clues regarding their roles in osmotic stress signaling.     

Modulation of protein kinases and phosphoprotein phosphatases by a small acidic protein from bovine brains

A small, acidic and heat-stable protein was purified from bovine brains by column chromatography on DEAE-cellulose, Bio-Gel HTP, Affi-Gel phenothiazine and Sephadex G-75. This protein stimulates megamodulin-dependent protein kinase I from brains and phosphoprotein phosphatases from either brain or yeast. However, it inhibits cyclic AMP-dependent protein kinases from skeletal muscle.     

Modulation of protein kinases and phosphoprotein phosphatases by a small acidic protein from bovine brains

Summary A small, acidic and heat-stable protein was purified from bovine brains by column chromatography on DEAE-cellulose, Bio-Gel HTP, Affi-Gel phenothiazine and Sephadex G-75. This protein stimulates megamodulin-dependent protein kinase I from brains and phosphoprotein phosphatases from either brain or yeast. However, it inhibits cyclic AMP-dependent protein kinases from skeletal muscle.Acknowledgments. This work was supported by a grant (RR-08229) from the National Institutes of Health, USA. W.N. Kuo is a recipient of a Distinguished Faculty Scholar Award from United Negro College Fund, Inc., USA.