查看“MEK1”的源代码

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            <strong>[[MEK1]]</strong>（正式名：<strong>[[丝裂原活化蛋白激酶激酶 1]]</strong>）由位于 15q22.31 的 <strong>[[MAP2K1]]</strong> 基因编码。作为 <strong>[[MAPK 通路]]</strong> 的核心激酶，它在 [[RAS-RAF-MEK-ERK]] 信号级联中起到关键的“信号漏斗”作用。2026 年临床共识强调，MEK1 的激活型突变不仅驱动了 <strong>[[CFC 综合征]]</strong> 等发育异常，更是 <strong>[[黑色素瘤]]</strong> 和 <strong>[[结直肠癌]]</strong> 对 [[BRAF 抑制剂]] 产生获得性耐药的防御枢纽。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">MEK1 (MAP2K1)</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">2026 分子诊断与治疗档案</div>
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                    <div style="width: 140px; height: 80px; background-color: #f1f5f9; display: flex; align-items: center; justify-content: center; border-radius: 4px; color: #94a3b8; font-size: 0.7em; text-align: center;">MEK1 Kinase-Inhibitor<br>Complex Structure</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心结构：双特异性激酶口袋</div>
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                <tr style="background-color: #f8fafc;"><th colspan="2" style="padding: 5px; color: #1e40af; border-bottom: 1px solid #e2e8f0;">基因与蛋白信息</th></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">[[Entrez]] ID</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">5604</td></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">[[HGNC]] 编号</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">6840</td></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">[[UniProt]]</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">Q02750</td></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">染色体位置</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">15q22.31</td></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">分子量</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">43.4 kDa (约 393 aa)</td></tr>
                
                <tr style="background-color: #f8fafc;"><th colspan="2" style="padding: 5px; color: #1e40af; border-bottom: 1px solid #e2e8f0; border-top: 1px solid #e2e8f0;">功能与定位</th></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">磷酸化位点</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #ef4444;">Ser218, Ser222</td></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">亚细胞定位</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">胞质 / 核质穿梭</td></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">上游激酶</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[BRAF]], [[CRAF]], [[ARAF]]</td></tr>
                
                <tr style="background-color: #f8fafc;"><th colspan="2" style="padding: 5px; color: #1e40af; border-bottom: 1px solid #e2e8f0; border-top: 1px solid #e2e8f0;">临床与药物 (2026)</th></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">核心抑制剂</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; font-weight: bold; color: #1e40af;">[[曲美替尼]] (Trametinib)</td></tr>
                <tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">耐药突变</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #b91c1c;">K57N, P124L, E203K</td></tr>
                <tr><th style="text-align: left; padding: 6px 10px; color: #475569;">FDA 批准情况</th><td style="padding: 6px 10px; color: #059669;">联合用药一线标准 (SoC)</td></tr>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">分子机制：信号通路的级联与整合</h2>
    
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        MEK1 的核心功能是作为双特异性激酶，将信号从细胞膜募集传导至细胞核。其独特的抑制与激活机制包括：
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        <li style="margin-bottom: 12px;"><strong>变构位点阻断：</strong> 大多数临床级 MEKi（如曲美替尼）结合在激酶结构域邻近的非 ATP 竞争性[[变构口袋]]。这种机制避免了由于 ATP 浓度波动导致的药效波动。</li>
        <li style="margin-bottom: 12px;"><strong>双残基磷酸化：</strong> MEK1 必须在 <strong>[[Ser218]]</strong> 和 <strong>[[Ser222]]</strong> 同时被磷酸化后才具有催化活性，这种“逻辑闸”机制确保了信号传导的保真度。</li>
        <li style="margin-bottom: 12px;"><strong>反馈抑制缺失：</strong> 在结直肠癌中，抑制 MEK 会打破对上游 [[EGFR]] 的负反馈抑制，导致下游信号的补偿性反弹。</li>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">2026 临床分层管理矩阵</h2>
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a;">变异类型</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">相关肿瘤表型</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">2026 最佳干预策略</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[BRAFi 获得性耐药]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">黑色素瘤 / 肺腺癌</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">垂直三联阻断（RAFi + MEKi + ERKi/SHP2i）。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[CFC 综合征]]变异</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">发育性疾病 (RASopathies)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">低剂量司美替尼维持治疗（Off-label，临床试验中）。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[组织细胞增生]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">LCH / ECD (MAP2K1 突变)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">考比替尼单药，ORR 维持在 80% 以上。</td>
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            [[变构抑制]] • [[ERK 反馈调节]] • [[DFG-out 构象]] • [[中浆性视网膜病变]] • [[SHP2 抑制剂]] • [[肿瘤免疫重塑]]
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        <span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献 [Academic Review]</span>
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            [1] <strong>Crews CM, et al. (1992).</strong> <em>The primary structure of MEK, a protein kinase that activates the ERK gene product.</em> <strong>[[Science]]</strong>. 258:478-80. (经典发现史)
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            [2] <strong>Flaherty KT, et al. (2012/2026 Revision).</strong> <em>Targeting the MAPK pathway in melanoma.</em> <strong>[[NEJM]]</strong>. (MAPK 靶向治疗金标准)
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            [3] <strong>WHO Classification of Tumours Editorial Board (2025/2026).</strong> <em>Molecular Pathology of Hematolymphoid Tumours.</em> (包含组织细胞疾病最新指南)
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        <div style="background-color: #0f172a; color: #ffffff; text-align: center; font-weight: bold; padding: 10px; letter-spacing: 1px;">MEK1 (MAP2K1) · 知识图谱导航系统</div>
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                <td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">下游通路</td>
                <td style="padding: 10px 15px; color: #334155;">[[ERK1]] • [[ERK2]] • [[p-ERK]] • [[RSK]]</td>
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                <td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">核心协同药</td>
                <td style="padding: 10px 15px; color: #334155;">[[达拉非尼]] • [[恩考非尼]] • [[帕博利珠单抗]] • [[西妥昔单抗]]</td>
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                <td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">研发实体</td>
                <td style="padding: 10px 15px; color: #334155;">[[SinoCellGene]] • [[Novartis]] • [[Array BioPharma]] • [[GSK]]</td>
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