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| Ref Type | Journal Article | ||||||||||||
| PMID | (12370306) | ||||||||||||
| Authors | Delaney AM, Printen JA, Chen H, Fauman EB, Dudley DT | ||||||||||||
| Title | Identification of a novel mitogen-activated protein kinase kinase activation domain recognized by the inhibitor PD 184352. | ||||||||||||
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| Abstract Text | Utilizing a genetic screen in the yeast Saccharomyces cerevisiae, we identified a novel autoactivation region in mammalian MEK1 that is involved in binding the specific MEK inhibitor, PD 184352. The genetic screen is possible due to the homology between components of the yeast pheromone response pathway and the eukaryotic Raf-MEK-ERK signaling cascade. Using the FUS1::HIS3 reporter as a functional readout for activation of a reconstituted Raf-MEK-ERK signaling cascade, randomly mutagenized MEK variants that were insensitive to PD 184352 were obtained. Seven single-base-change mutations were identified, five of which mapped to kinase subdomains III and IV of MEK. Of the seven variants, only one, a leucine-to-proline substitution at amino acid 115 (Leu115Pro), was completely insensitive to PD 184352 in vitro (50% inhibitory concentration >10 micro M). However, all seven mutants displayed strikingly high basal activity compared to wild-type MEK. Overexpression of the MEK variants in HEK293T cells resulted in an increase in mitogen-activated protein (MAP) kinase phosphorylation, a finding consistent with the elevated basal activity of these constructs. Further, treatment with PD 184352 failed to inhibit Leu115Pro-stimulated MAP kinase activation in HEK293T cells, whereas all other variants had some reduction in phospho-MAP kinase levels. By using cyclic AMP-dependent protein kinase (1CDK) as a template, an MEK homology model was generated, with five of the seven identified residues clustered together, forming a potential hydrophobic binding pocket for PD 184352. Additionally, the model allowed identification of other potential residues that would interact with the inhibitor. Directed mutation of these residues supported this region's involvement with inhibitor binding. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| MAP2K1 | F53S | missense | gain of function | MAP2K1 F53S lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). F53S demonstrates phosphorylation profile similar to wild-type Map2k1 (PMID: 29753091), and results in increased Erk phosphorylation in cell culture (PMID: 16439621, PMID: 12370306). | |
| MAP2K1 | I103N | missense | gain of function | MAP2K1 I103N lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I103N confers a gain of function to the Map2k1 protein as demonstrated by elevated basal kinase activity in an in vitro assay (PMID: 12370306), increased Map2k1 autophosphorylation (PMID: 29753091), and transformation activity in cell culture and increased proliferation in a competition assay (PMID: 36442478), and is also associated with resistance to Mek inhibitors (PMID: 12370306, PMID: 19915144). | Y |
| MAP2K1 | I111A | missense | gain of function - predicted | MAP2K1 I111A lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I111A is predicted to confer a gain of function to the Map2k1 protein as demonstrated by increased basal Map2k1 kinase activity in an in vitro assay and is associated with decreased sensitivity to Mek inhibition (PMID: 12370306). | |
| MAP2K1 | I111D | missense | gain of function - predicted | MAP2K1 I111D lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I111D is predicted to confer a gain of function to the Map2k1 protein as demonstrated by increased basal Map2k1 kinase activity in an in vitro assay and is associated with resistance to Mek inhibition (PMID: 12370306). | Y |
| MAP2K1 | I111P | missense | gain of function - predicted | MAP2K1 I111P lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I111P is predicted to confer a gain of function to the Map2k1 protein as demonstrated by increased basal Map2k1 kinase activity in an in vitro assay and is also associated with resistance to Mek inhibition (PMID: 12370306). | Y |
| MAP2K1 | I111R | missense | gain of function - predicted | MAP2K1 I111R lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I111R is predicted to confer a gain of function to the Map2k1 protein as demonstrated by increased basal Map2k1 kinase activity in an in vitro assay and is also associated with resistance to Mek inhibition (PMID: 12370306). | Y |
| MAP2K1 | I139G | missense | no effect - predicted | MAP2K1 I139G lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I139G is predicted to have no effect on Map2k1 protein function as demonstrated by basal kinase activity similar to wild-type Map2k1 in an in vitro assay, and is associated with resistance to Mek inhibition (PMID: 12370306). | Y |
| MAP2K1 | I139N | missense | no effect - predicted | MAP2K1 I139N lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I139N is predicted to have no effect on Map2k1 protein function as demonstrated by basal kinase activity similar to wild-type Map2k1 in an in vitro assay, and is associated with decreased sensitivity to Mek inhibition (PMID: 12370306). | |
| MAP2K1 | I139R | missense | no effect - predicted | MAP2K1 I139R lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I139R is predicted to have no effect on Map2k1 protein function as demonstrated by basal kinase activity similar to wild-type Map2k1 in an in vitro assay, and is associated with decreased sensitivity to Mek inhibition (PMID: 12370306). | |
| MAP2K1 | L115A | missense | gain of function - predicted | MAP2K1 L115A lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L115A is predicted to confer a gain of function to the Map2k1 protein, as demonstrated by increased kinase activity in an in vitro assay (PMID: 12370306) and is also associated with decreased binding and partial response to Mek inhibitors (PMID: 12370306). | |
| MAP2K1 | L115P | missense | gain of function | MAP2K1 L115P lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L115P confers a gain of function on the kinase activity of the Map2k1 protein, as demonstrated by increased autophosphorylation in cell culture (PMID: 29753091) and increased basal kinase activity in an in vitro assay (PMID: 12370306), and is also associated with decreased binding and resistance to Mek inhibitors (PMID: 12370306, PMID: 19915144, PMID: 26399658). | Y |
| MAP2K1 | L118D | missense | loss of function - predicted | MAP2K1 L118D lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L118D is predicted to confer a loss of function to the Map2k1 protein as demonstrated by decreased basal Map2k1 kinase activity in an in vitro assay and is associated with resistance to Mek inhibition (PMID: 12370306). | Y |
| MAP2K1 | L118G | missense | loss of function - predicted | MAP2K1 L118G lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L118G is predicted to confer a loss of function to the Map2k1 protein as demonstrated by decreased basal Map2k1 kinase activity in an in vitro assay and is associated with decreased sensitivity to Mek inhibition (PMID: 12370306). | |
| MAP2K1 | L118P | missense | loss of function - predicted | MAP2K1 L118P lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L118P is associated with MEK inhibitor resistance and results in decreased basal kinase activity in an in vitro assay (PMID: 12370306), and therefore, its predicted to lead to a loss of Map2k1 protein function. | Y |
| MAP2K1 | L118Q | missense | loss of function - predicted | MAP2K1 L118Q lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L118Q is predicted to confer a loss of function to the Map2k1 protein as demonstrated by decreased basal Map2k1 kinase activity in an in vitro assay and is associated with resistance to Mek inhibition (PMID: 12370306). | Y |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| MAP2K1 I111R | Advanced Solid Tumor | predicted - resistant | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, CI-1040 (PD184352) did not inhibit kinase activity of MAP2K1 I111R in an in vitro assay (PMID: 12370306). | 12370306 |
| MAP2K1 I139G | Advanced Solid Tumor | predicted - resistant | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, CI-1040 (PD184352) did not inhibit kinase activity of MAP2K1 I139G in an in vitro assay (PMID: 12370306). | 12370306 |
| MAP2K1 L118P | Advanced Solid Tumor | predicted - resistant | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, CI-1040 (PD184352) did not inhibit kinase activity of MAP2K1 L118P in an in vitro assay (PMID: 12370306). | 12370306 |
| MAP2K1 I111P | Advanced Solid Tumor | predicted - resistant | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, CI-1040 (PD184352) did not inhibit kinase activity of MAP2K1 I111P in an in vitro assay (PMID: 12370306). | 12370306 |
| MAP2K1 L118G | Advanced Solid Tumor | decreased response | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, MAP2K1 L118G demonstrated decreased sensitivity to CI-1040 (PD184352) in an in vitro kinase assay (PMID: 12370306). | 12370306 |
| MAP2K1 I103N | Advanced Solid Tumor | decreased response | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, MAP2K1 I103N demonstrated decreased sensitivity to CI-1040 (PD184352) in an in vitro kinase assay (PMID: 12370306). | 12370306 |
| MAP2K1 L115P | Advanced Solid Tumor | resistant | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, CI-1040 (PD184352) did not inhibit kinase activity of MAP2K1 L115P in an in vitro assay and failed to suppress Erk phosphorylation in cells expressing MAP2K1 L115P in culture (PMID: 12370306). | 12370306 |
| MAP2K1 F53S | Advanced Solid Tumor | sensitive | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, CI-1040 (PD184352) inhibited kinase activity of MAP2K1 F53S in an in vitro assay and decreased Erk phosphorylation in cells expressing MAP2K1 F53S in culture (PMID: 12370306). | 12370306 |
| MAP2K1 L118Q | Advanced Solid Tumor | predicted - resistant | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, CI-1040 (PD184352) did not inhibit kinase activity of MAP2K1 L118Q in an in vitro assay (PMID: 12370306). | 12370306 |
| MAP2K1 L118D | Advanced Solid Tumor | predicted - resistant | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, CI-1040 (PD184352) did not inhibit kinase activity of MAP2K1 L118D in an in vitro assay (PMID: 12370306). | 12370306 |
| MAP2K1 I139R | Advanced Solid Tumor | decreased response | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, MAP2K1 I139R demonstrated decreased sensitivity to CI-1040 (PD184352) in an in vitro kinase assay (PMID: 12370306). | 12370306 |
| MAP2K1 I111D | Advanced Solid Tumor | predicted - resistant | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, CI-1040 (PD184352) did not inhibit kinase activity of MAP2K1 I111D in an in vitro assay (PMID: 12370306). | 12370306 |
| MAP2K1 L115A | Advanced Solid Tumor | decreased response | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, MAP2K1 L115A demonstrated decreased sensitivity to CI-1040 (PD184352) in an in vitro kinase assay (PMID: 12370306). | 12370306 |
| MAP2K1 I139N | Advanced Solid Tumor | decreased response | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, MAP2K1 I139N demonstrated decreased sensitivity to CI-1040 (PD184352) in an in vitro kinase assay (PMID: 12370306). | 12370306 |
| MAP2K1 I111A | Advanced Solid Tumor | decreased response | CI-1040 | Preclinical - Biochemical | Actionable | In a preclinical study, MAP2K1 I111A demonstrated decreased sensitivity to CI-1040 (PD184352) in an in vitro kinase assay (PMID: 12370306). | 12370306 |