Identification of epidermal growth factor Thr-669 phosphorylation site peptide kinases as distinct MAP kinases and p34cdc2

Sanghera, Jasbinder S.; Hall, Frederick L.; Warburton, David; Campbell, Donna; Pelech, Steven

doi:10.1016/0167-4889(92)90240-c

Cited by 34 publications

(17 citation statements)

References 34 publications

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“…(45). Cdc2, a serine/threonine kinase which is a key regulator of several growth-related proteins and is most active in the M phase (46,47), can phosphorylate serine residues on EGFR and lead to reduction of its tyrosine kinase activity (48,49). Our data in this report clearly show that EGFR also has a cell cycle-dependent regulatory mechanism, suggesting that such a mechanism is common among the receptor tyrosine kinases and is not unique to a particular tyrosine kinase.…”

Section: Discussionmentioning

confidence: 99%

Mitosis-specific Negative Regulation of Epidermal Growth Factor Receptor, Triggered by a Decrease in Ligand Binding and Dimerization, Can Be Overcome by Overexpression of Receptor

Kiyokawa

Lee

Karunagaran

et al. 1997

Journal of Biological Chemistry

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The function of epidermal growth factor receptor (EGFR) was found to be negatively regulated in M phase in which it showed less phosphotyrosine content and reduced intrinsic kinase activity accompanied by retarded electrophoretic mobility owing to total hyperphosphorylation. Ligand-induced autophosphorylation and downstream signaling of EGFR were tightly suppressed in M phase due to a decrease in ligand binding affinity and the inability of epidermal growth factor (EGF) to induce receptor dimerization. There was no change in the number of surface-exposed EGF receptors between G 0 /G 1 and M phases of the cell cycle. Hyperphosphorylation (due to serine and/or threonine phosphorylation) correlates with the unresponsiveness of cells to EGF-mediated stimulation of tyrosine phosphorylation in cells that express the normal or basal level of EGFR. This M phase-specific negative regulation was overcome by overexpression of EGFR, which was responsive to ligand throughout the cell cycle and revealed ligand-induced signaling in the M phase. These findings indicate that EGFR does not respond to ligand stimulation in M phase and suggest that a negative regulation of ligand-receptor interactions in M phase may control the normal function of receptor tyrosine kinase and that receptor overexpression will disrupt this cell cycle-dependent regulation of receptor tyrosine kinases.

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Section: Discussionmentioning

confidence: 99%

Mitosis-specific Negative Regulation of Epidermal Growth Factor Receptor, Triggered by a Decrease in Ligand Binding and Dimerization, Can Be Overcome by Overexpression of Receptor

Kiyokawa

Lee

Karunagaran

et al. 1997

Journal of Biological Chemistry

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“…Furthermore, we showed that the SPC region of BCL-6 is involved in the association of this protein with MAPK in vivo. Sanghera et al, 1992a), and ®rst tested whether MAPK and Jun N-terminal kinase (JNK) are able to phosphorylate BCL-6 in vitro. Full-length BCL-6 fused to glutathione S-transferase [GST-BCL-6 (1-706)] bound to glutathione-Sepharose beads was incubated with [g-32 P]ATP and puri®ed MAPK or JNK.…”

Section: Introductionmentioning

confidence: 99%

BCL-6 is phosphorylated at multiple sites in its serine- and proline-clustered region by mitogen-activated protein kinase (MAPK) in vivo

et al. 1997

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BCL-6 gene alterations have been observed in 27 ± 45% of di use large B-cell lymphomas (DLBs) with chromosomal translocations at 3q27. The deregulated expression of normal BCL-6 protein caused by this chromosomal translocation is believed to be responsible for lymphomagenesis. Recently, we demonstrated that BCL-6 is expressed at high levels in germinal center B-cells as a 92-98 kDa nuclear protein in a constitutively phosphorylated form. In this study, we show that BCL-6 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro at the sites phosphorylated in vivo. These numerous phosphorylation sites were found to be located in its serine-and proline-clustered (SPC) region (amino acids-250-483). BCL-6 phosphorylation signi®-cantly increased in Ramos cells following stimulation with 12-o-tetradecanoylphorbol-13-acetate (TPA) or BCL-6-and erk1-transfected COS-7 cells stimulated with epidermal growth factor (EGF), and the increase of phosphorylation was inhibited by MEK1 inhibitor, PD98059. Furthermore, we observed that BCL-6 was associated with MAPK in vivo and its SPC region was important for this association. These results suggest that the functions of BCL-6 are regulated by phosphorylation mediated by the MAPK signaling pathway.

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“…To clone the cDNA for the human homolog of p44erkl, it was necessary to identify cell lines in which this MAP kinase isoform was expressed. We have described the presence of p42maPk and a p44ef*l-ike protein in the human epidermoid carcinoma A431 cell line on the basis of their immunoreactivity with MAP kinase antibodies (64). Similarly, we detected p44e!…”

Section: Resultsmentioning

confidence: 64%

“…Enzymological analyses of highly purified preparations of p42mapk, p44ek*l, and p44mPk from various sources also supports their relatedness (6,26,55,65 [7,41], mouse [16], and guinea pig [43]). This * Corresponding author.implies the existence of specialized functions for the distinct isoforms or their differential regulation.Immunoblotting studies with antibodies generated against MAP kinase peptides have revealed additional, potentially related MAP kinase isoforms in extracts from sea star, frog, avian, and mammalian cells (5,63,64). One of these is a human 40-kDa MBP kinase that appears to physically associate with the human epidermal growth factor receptor (64).…”

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confidence: 99%

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Molecular cloning, expression, and characterization of the human mitogen-activated protein kinase p44erk1.

et al. 1993

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p44ek is a member of a family of tyrosyl-phosphorylated and mitogen-activated protein (MAP) Subsequently, an additional insulin-activated MAP kinase (p44") from a rat hepatoma cell line was purified and characterized (6). cDNA sequence data for rat p42naPk and p44cr*l revealed -90% amino acid identity between these MAP kinase isoforms (7) and -70% amino acid identity with partial sequences of sea star p44""k obtained by protein microsequencing (53). Enzymological analyses of highly purified preparations of p42mapk, p44ek*l, and p44mPk from various sources also supports their relatedness (6,26,55,65 [7,41], mouse [16], and guinea pig [43]). This * Corresponding author.implies the existence of specialized functions for the distinct isoforms or their differential regulation.Immunoblotting studies with antibodies generated against MAP kinase peptides have revealed additional, potentially related MAP kinase isoforms in extracts from sea star, frog, avian, and mammalian cells (5,63,64). One of these is a human 40-kDa MBP kinase that appears to physically associate with the human epidermal growth factor receptor (64). Another is a 46-kDa protein that has been tentatively designated p46e"*4 (5). Kyriakis and Avruch (35) have reported the purification of an activated 54-kDa MAP-2 kinase from the livers of cycloheximide-treated rats. This kinase exhibits -50% amino acid identity with rat p42maPk within its catalytic domain (3a Mammalian and frog MAP kinases are activated by -45-kDa kinases that catalyze their tyrosyl and threonyl phosphorylation (18,37,42,45,59,67,69

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Identification of epidermal growth factor Thr-669 phosphorylation site peptide kinases as distinct MAP kinases and p34cdc2

Cited by 34 publications

References 34 publications

Mitosis-specific Negative Regulation of Epidermal Growth Factor Receptor, Triggered by a Decrease in Ligand Binding and Dimerization, Can Be Overcome by Overexpression of Receptor

Mitosis-specific Negative Regulation of Epidermal Growth Factor Receptor, Triggered by a Decrease in Ligand Binding and Dimerization, Can Be Overcome by Overexpression of Receptor

BCL-6 is phosphorylated at multiple sites in its serine- and proline-clustered region by mitogen-activated protein kinase (MAPK) in vivo

Molecular cloning, expression, and characterization of the human mitogen-activated protein kinase p44erk1.

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