查看“MAPK信号通路”的源代码

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            <strong>[[MAPK信号通路]]</strong>（<strong>[[Mitogen-activatedProteinKinasePathway]]</strong>，又称<strong>[[有丝分裂原激活蛋白激酶通路]]</strong>）是[[真核细胞]]内最保守且高度复杂的[[信号转导]]系统之一。该通路通过[[蛋白激酶]]的逐级[[磷酸化]]将胞外信号（如[[生长因子]]、[[细胞因子]]、[[应激]]刺激）传递至[[细胞核]]，从而调控细胞的[[增殖]]、[[分化]]、[[迁移]]及[[凋亡]]。经典的<strong>[[Ras-Raf-MEK-ERK]]</strong>通路是研究最深入的分支，其异常持续激活是包括<strong>[[非小细胞肺癌]]</strong>、<strong>[[黑色素瘤]]</strong>及<strong>[[结直肠癌]]</strong>在内的多种<strong>[[恶性肿瘤]]</strong>的核心致病机制。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">MAPK信号通路</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px;">Signaling Pathway: [[MAPK]] · 点击展开详情</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">胞内级联放大系统</div>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">核心成员</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0;">[[RAS]]/[[RAF]]/[[MEK]]/[[ERK]]</td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">主要亚族</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0;">[[ERK]]/[[JNK]]/[[p38]]</td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">关键驱动基因</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0;">[[KRAS]]/[[NRAS]]/[[BRAF]]</td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">主要功能</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0;">[[细胞生长]]、[[应激响应]]</td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">激活方式</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0;">[[磷酸化级联]]</td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569;">研究方法</th>
                    <td style="padding: 10px 12px;">[[WB]]/[[磷酸化抗体]]监测</td>
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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：三级激酶瀑布式级联</h2>
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        [[MAPK信号通路]]的运行依赖于一系列高度有序的<strong>[[蛋白质修饰]]</strong>过程，其核心架构被称为<strong>[[三级激酶级联]]</strong>。
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            <p style="font-size: 0.8em; color: #64748b; margin-top: 8px;">图1：经典Ras-Raf-MEK-ERK信号通路模式</p>
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        <li style="margin-bottom: 12px;"><strong>[[上游激活]]：</strong>外部[[配体]]结合[[受体酪氨酸激酶]]（[[RTK]]）诱导其[[自身磷酸化]]，招募[[适配蛋白]]（如[[Grb2]]）激活<strong>[[Ras]]</strong>蛋白（从[[GDP结合态]]转为[[GTP结合态]]）。</li>
        <li style="margin-bottom: 12px;"><strong>三级级联传递：</strong>
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                <li><strong>[[MAPKKK]]（如[[Raf]]）：</strong>激活后的[[Ras]]募集[[Raf]]激酶至胞膜并使其活化。</li>
                <li><strong>[[MAPKK]]（如[[MEK]]）：</strong>[[Raf]]磷酸化并激活[[MEK1]]/[[MEK2]]。</li>
                <li><strong>[[MAPK]]（如[[ERK]]）：</strong>[[MEK]]进一步双位点磷酸化并激活[[ERK1]]/[[ERK2]]。</li>
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        <li style="margin-bottom: 12px;"><strong>[[核移位]]与转录响应：</strong>激活态的[[ERK]]转运至[[细胞核]]，通过磷酸化<strong>[[转录因子]]</strong>（如[[c-Myc]]、[[Elk-1]]）直接调控靶基因表达，驱动细胞由[[G1期]]向[[S期]]转化。</li>
        <li style="margin-bottom: 12px;"><strong>[[分支通路]]：</strong>除[[ERK]]通路外，该家族还包括主要响应[[应激]]和[[促炎因子]]的<strong>[[JNK]]</strong>通路和<strong>[[p38]]</strong>通路。</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;">病理全景：MAPK异常与肿瘤驱动矩阵</h2>
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">驱动基因</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">常见[[变异]]类型</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">高发癌种</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[KRAS]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">[[G12C]]、[[G12D]]、[[G12V]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">[[胰腺癌]]、[[非小细胞肺癌]]、[[结直肠癌]]</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[BRAF]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">[[V600E]]点突变</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">[[黑色素瘤]]、[[甲状腺乳头状癌]]</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[NRAS]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">第12、13或61位点突变</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">[[恶性黑色素瘤]]、[[急性髓系白血病]]</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[EGFR]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">[[19号外显子缺失]]/[[L858R]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">通过[[上游]]过载激活[[MAPK]]通路</td>
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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;">治疗策略：靶向MAPK各级节点的临床现状</h2>
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        <li style="margin-bottom: 12px;"><strong>[[RAS抑制剂]]：</strong>如<strong>[[索托拉西布]]</strong>（[[Sotorasib]]）特异性锁定[[KRASG12C]]非活性构象，是该领域的重要突破。</li>
        <li style="margin-bottom: 12px;"><strong>[[BRAF抑制剂]]：</strong>如<strong>[[维罗非尼]]</strong>（[[Vemurafenib]]）显著改善了[[V600E]]突变患者的预后。</li>
        <li style="margin-bottom: 12px;"><strong>[[MEK抑制剂]]：</strong>如<strong>[[曲美替尼]]</strong>（[[Trametinib]]）常与[[BRAF抑制剂]]联用，旨在延迟[[获得性耐药]]并减轻[[皮肤毒性]]。</li>
        <li style="margin-bottom: 12px;"><strong>[[联合策略]]与[[反馈控制]]：</strong>通路抑制后常诱发<strong>[[RTK反馈性上调]]</strong>，因此联合<strong>[[EGFR抑制剂]]</strong>或<strong>[[SHP2抑制剂]]</strong>已成为主流研究方向。</li>
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        <h3 style="color: #0f172a; font-size: 1.15em; margin-bottom: 20px; border-bottom: 2px solid #3b82f6; display: inline-block; padding-bottom: 5px;">关键相关概念</h3>
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            <div style="color: #334155;"><strong style="color: #1e40af;">[[磷酸化激酶级联]]</strong>：信号放大的核心生化机制。</div>
            <div style="color: #334155;"><strong style="color: #1e40af;">[[反馈调节回路]]</strong>：细胞维持[[稳态]]及产生靶向药[[耐药]]的主因。</div>
            <div style="color: #334155;"><strong style="color: #1e40af;">[[伴随诊断]]</strong>：通过[[NGS]]检测通路变异以指导[[精准选药]]。</div>
            <div style="color: #334155;"><strong style="color: #1e40af;">[[串扰]]</strong>：MAPK通路与<strong>[[PI3K-AKT]]</strong>通路间的相互调节与代偿。</div>
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        <span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献与权威点评</span>
        
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            [1] <strong>Dhillon AS, et al. (2007).</strong> <em>MAP kinase signalling pathways in cancer.</em> <strong>[[Nature Reviews Molecular Cell Biology]]</strong>. 2007;8(6):471-483.<br>
            <span style="color: #475569;">[学术点评]：基石综述。系统定义了三级级联在不同细胞背景下的特异性响应模式。</span>
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            [2] <strong>Cargnello M, Roux PP. (2011).</strong> <em>Activation and function of the MAP kinase signaling pathways.</em> <strong>[[MMBR]]</strong>. 2011;75(1):50-83.<br>
            <span style="color: #475569;">[学术点评]：全面回顾了从[[酵母]]到[[人类]]进化保守的[[MAPK]]调控逻辑。</span>
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            [3] <strong>Santarpia L, et al. (2012).</strong> <em>Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy.</em> <strong>[[Expert Opin Ther Targets]]</strong>.<br>
            <span style="color: #475569;">[学术点评]：[Academic Review] 详细讨论了临床上通过小分子药物克服该通路反馈机制的难点与希望。</span>
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            [[MAPK信号通路]] ([[SignalingPathway]]) · 知识图谱导航
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                <td style="width: 100px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 15px; text-align: left; vertical-align: middle;">[[三级级联]]</td>
                <td style="padding: 10px 15px; color: #334155; text-align: left;">[[Ras]] • [[Raf]] • [[MEK1/2]] • [[ERK1/2]] • [[JNK]] • [[p38]]</td>
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                <td style="width: 100px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 15px; text-align: left; vertical-align: middle;">[[调控分子]]</td>
                <td style="padding: 10px 15px; color: #334155; text-align: left;">[[SOS1]] • [[Grb2]] • [[SHP2]] • [[MKP磷酸酶]] • [[DUSP家族]]</td>
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                <td style="width: 100px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 15px; text-align: left; vertical-align: middle;">[[靶向药物]]</td>
                <td style="padding: 10px 15px; color: #334155; text-align: left;">[[索托拉西布]] • [[维罗非尼]] • [[曲美替尼]] • [[考比替尼]] • [[阿法替尼]]</td>
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