Mark Lemmon
University of Pennsylvania, Biochemistry And Biophysics, Faculty Member
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Research Interests: Kinetics, Breast Cancer, Biological Sciences, RNA interference, Molecular and cellular biology, and 10 moreHumans, Female, Actin Cytoskeleton, Epidermal Growth Factor, Epidermal Growth Factor Receptor, Cell Proliferation, Protein Kinase Inhibitors, Rho GTPase, Breast Cancer Cells, and Growth factor receptor
The initiation of epidermal growth factor receptor (EGFR) kinase activity proceeds via an asymmetric dimerization mechanism in which a... more
The initiation of epidermal growth factor receptor (EGFR) kinase activity proceeds via an asymmetric dimerization mechanism in which a "donor" tyrosine kinase domain (TKD) contacts an "acceptor" TKD, leading to its activation. In the context of a ligand-induced dimer, identical wild-type EGFR TKDs are thought to assume the donor or acceptor roles in a random manner. Here, we present biochemical reconstitution data demonstrating that activated EGFR mutants found in lung cancer preferentially assume the acceptor role when coexpressed with WT EGFR. Mutated EGFRs show enhanced association with WT EGFR, leading to hyperphosphorylation of the WT counterpart. Mutated EGFRs also hyperphosphorylate the related erythroblastic leukemia viral oncogene (ErbB) family member, ErbB-2, in a similar manner. This directional "superacceptor activity" is particularly pronounced in the drug-resistant L834R/T766M mutant. A 4-Å crystal structure of this mutant in the active conformation reveals an asymmetric dimer interface that is essentially the same as that in WT EGFR. Asymmetric dimer formation induces an allosteric conformational change in the acceptor subunit. Thus, superacceptor activity likely arises simply from a lower energetic cost associated with this conformational change in the mutant EGFR compared with WT, rather than from any structural alteration that impairs the donor role of the mutant. Collectively, these findings define a previously unrecognized mode of mutant-specific intermolecular regulation for ErbB receptors, knowledge of which could potentially be exploited for therapeutic benefit.
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Research Interests: Structure, Biological Sciences, Crystal structure, Humans, Animals, and 11 moreCHEMICAL SCIENCES, Protein Secondary Structure Prediction, Mammary gland, Signaling, Nervous System, Protein Quaternary Structure, Protein Binding, EGF receptor, Protein Kinase Inhibitors, Receptor Tyrosine Kinase, and Quinazolines
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Research Interests: Multidisciplinary, Signal Transduction, Humans, Glutathione, Surface plasmon resonance, and 11 morePhosphotyrosine, Isothermal Titration Calorimetry, Calorimetry, Glutathione Transferase, Amino Acid Sequence, Protein Binding, Fusion Protein, Intracellular Signaling, Binding Site, Dissociation Constant, and Tyrosine
Research Interests: Genetics, Pigmentation, Amyloid, Humans, Mutation, and 8 moreMice, Animals, Horses, Chickens, HeLa cells, PLoS Genetics, Melanocytes, and Amino Acid Sequence
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Research Interests: Macromolecular X-Ray Crystallography, Signal Transduction, Cell and Molecular Biology, Biological Sciences, Sequence alignment, and 9 moreFatty acids, Hydrogen Bonding, Protein Secondary Structure Prediction, Substrate Specificity, Lipoproteins, Amino Acid Profile, Amino Acid Sequence, Second Messengers, and Blood Proteins
Research Interests: Cellular Biology, Kinetics, Apoptosis, Multidisciplinary, Nature, and 33 moreCell Culture, Cell Division, Signal Transduction, Biological Sciences, Adipose tissue, Molecular and cellular biology, Humans, Keratinocytes, Mutation, Mice, Animals, Ligand Binding, Surface plasmon resonance, Monoclonal Antibodies, Protein Interaction, Epidermal Growth Factor, Epidermal Growth Factor Receptor, Adverse Event, Cancer Patient, Cancer cells, Targeted Therapy, Side Effect, Protein Quaternary Structure, Protein Binding, Cancers, Enzymatic Activity, EGF receptor, Fusion Protein, Antineoplastic Agents, Ligands, Conformational Change, Dimerization, and Quinazolines
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... Kathryn M. Ferguson * , Mark A. Lemmon , Joseph Schlessinger and Paul B. Sigler . ... The presentchallengeis to deter mine whethersuch anchoringcan arise from weak, rela tively unspecificinteractionssuch as those seen for the PH... more
... Kathryn M. Ferguson * , Mark A. Lemmon , Joseph Schlessinger and Paul B. Sigler . ... The presentchallengeis to deter mine whethersuch anchoringcan arise from weak, rela tively unspecificinteractionssuch as those seen for the PH domainsfrom pleckstrinand spectrin,or ...
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As with other groups of protein kinases, approximately 10% of the RTKs (receptor tyrosine kinases) in the human proteome contain intracellular pseudokinases that lack one or more conserved catalytically important residues. These include... more
As with other groups of protein kinases, approximately 10% of the RTKs (receptor tyrosine kinases) in the human proteome contain intracellular pseudokinases that lack one or more conserved catalytically important residues. These include ErbB3, a member of the EGFR (epidermal growth factor receptor) family, and a series of unconventional Wnt receptors. We showed previously that, despite its reputation as a pseudokinase, the ErbB3 TKD (tyrosine kinase domain) does retain significant, albeit weak, kinase activity. This led us to suggest that a subgroup of RTKs may be able to signal even with very inefficient kinases. Recent work suggests that this is not the case, however. Other pseudokinase RTKs have not revealed significant kinase activity, and mutations that impair ErbB3's weak kinase activity have not so far been found to exhibit signalling defects. These findings therefore point to models in which the TKDs of pseudokinase RTKs participate in receptor signalling by allosterically regulating associated kinases (such as ErbB3 regulation of ErbB2) and/or function as regulated 'scaffolds' for other intermolecular interactions central to signal propagation. Further structural and functional studies, particularly of the pseudokinase RTKs involved in Wnt signalling, are required to shed new light on these intriguing signalling mechanisms.
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Phosphatidylinositol 4,5-bisphosphate (PIP2) affects profoundly several cardiac ion channels and transporters, and studies of PIP2-sensitive currents in excised patches suggest that PIP2 can be synthesized and broken down within 30 s. To... more
Phosphatidylinositol 4,5-bisphosphate (PIP2) affects profoundly several cardiac ion channels and transporters, and studies of PIP2-sensitive currents in excised patches suggest that PIP2 can be synthesized and broken down within 30 s. To test when, and if, total phosphatidylinositol 4-phosphate (PIP) and PIP(2) levels actually change in intact heart, we used a new, nonradioactive HPLC method to quantify anionic phospholipids. Total PIP and PIP2 levels (10-30 micromol/kg wet weight) do not change, or even increase, with activation of Galpha(q)/phospholipase C (PLC)-dependent pathways by carbachol (50 microM), phenylephrine (50 microM), and endothelin-1 (0.3 microM). Adenosine (0.2 mM) and phorbol 12-myristate 13-acetate (1microM) both cause 30% reduction of PIP2 in ventricles, suggesting that diacylglycerol (DAG)-dependent mechanisms negatively regulate cardiac PIP2. PIP2, but not PIP, increases reversibly by 30% during electrical stimulation (2 Hz for 5 min) in guinea pig left atria; the increase is blocked by nickel (2 mM). Both PIP and PIP2 increase within 3 min in hypertonic solutions, roughly in proportion to osmolarity, and similar effects occur in multiple cell lines. Inhibitors of several volume-sensitive signaling mechanisms do not affect these responses, suggesting that PIP2 metabolism might be sensitive to membrane tension, per se.