FGFR2 激活的点突变
中文名称
通路描述
FGFR2 的常染色体显性突变与一系列骨骼发育障碍的发展相关，包括 Beare-Stevensen 切齿嵴综合征、Pfeiffer 综合征、Jackson-Weiss 综合征、Crouzon 综合征和 Apert 综合征 (见 Burke, 1998; Webster and Donoghue 1997; Cunningham, 2007)。导致 Crouzon、Jackson-Weiss 和 Pfeiffer 综合征的突变倾向于聚集在受体的第三个 Ig 样结构域中，要么在 exon IIIa (由 IIIb 和 IIIc 等位基因共享) 或在 FGFR2c 特异性 exon IIIc 中。这些突变经常涉及形成或移除一个半胱氨酸残基，导致形成未配对半胱氨酸残基，这被认为促进分子二聚化，从而引起构象、配体独立激活 (综述见 Burke, 1998; Webster and Donoghue, 1997; Cunningham, 2007)。导致 Apert 综合征的 FGFR2 突变聚集在高度保守的 Pro-Ser 二肽在 IgII-Ig III 连接区；FGFR1 和 3 的旁系同源残基突变分别导致 Pfeiffer 和 Muenke 综合征 (Muenke, 1994; Wilkie, 1995; Bellus, 1996)。Beare-Stevensen 切齿嵴综合征的发展与受体转膜近端区域的突变相关 (Przylepa, 1996)，类似的突变与 thanatophoric dysplasia I (Tavormina, 1995a) 的发展相关。所有这些突变都影响 FGFR2 信号传导而不改变受体的内在激酶活性。
英文描述
Activated point mutants of FGFR2 Autosomal dominant mutations in FGFR2 are associated with the development of a range of skeletal disorders including Beare-Stevensen cutis gyrata syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome, Crouzon syndrome and Apert Syndrome (reveiwed in Burke, 1998; Webster and Donoghue 1997; Cunningham, 2007). Mutations that give rise to Crouzon, Jackson-Weiss and Pfeiffer syndromes tend to cluster in the third Ig-like domain of the receptor, either in exon IIIa (shared by the IIIb and the IIIc isoforms) or in the FGFR2c-specific exon IIIc. These mutations frequently involve creation or removal of a cysteine residue, leading to the formation of an unpaired cysteine residue that is thought to promote intramolecular dimerization and thus constitutive, ligand-independent activation (reviewed in Burke, 1998; Webster and Donoghue, 1997; Cunningham, 2007). Mutations in FGFR2 that give rise to Apert Syndrome cluster to the highly conserved Pro-Ser dipeptide in the IgII-Ig III linker; mutations in the paralogous residues of FGFR1 and 3 give rise to Pfeiffer and Muenke syndromes, respectively (Muenke, 1994; Wilkie, 1995; Bellus, 1996). Development of Beare-Stevensen cutis gyrata is associated with mutations in the transmembrane-proximal region of the receptor (Przylepa, 1996), and similar mutations in FGFR3 are linked to the development of thanatophoric dysplasia I (Tavormina, 1995a). These mutations all affect FGFR2 signaling without altering the intrinsic kinase activity of the receptor.
Activating point mutations have also been identified in FGFR2 in ~15% of endometrial cancers, as well as to a lesser extent in ovarian and gastric cancers (Dutt, 2008; Pollock, 2007; Byron, 2010; Jang, 2001). These mutations are found largely in the extracellular region and in the kinase domain of the receptor, and parallel activating mutations seen in autosomal dominant disorders described above.
Activating mutations in FGFR2 are thought to contribute to receptor activation through diverse mechanisms, including constitutive ligand-independent dimerization (Robertson, 1998), expanded range and affinity for ligand (Ibrahimi, 2004b; Yu, 2000) and enhanced kinase activity (Byron, 2008; Chen, 2007).
Activating point mutations have also been identified in FGFR2 in ~15% of endometrial cancers, as well as to a lesser extent in ovarian and gastric cancers (Dutt, 2008; Pollock, 2007; Byron, 2010; Jang, 2001). These mutations are found largely in the extracellular region and in the kinase domain of the receptor, and parallel activating mutations seen in autosomal dominant disorders described above.
Activating mutations in FGFR2 are thought to contribute to receptor activation through diverse mechanisms, including constitutive ligand-independent dimerization (Robertson, 1998), expanded range and affinity for ligand (Ibrahimi, 2004b; Yu, 2000) and enhanced kinase activity (Byron, 2008; Chen, 2007).
所含基因
13 个基因