Dramatic inhibition of osteoclast sealing ring formation and bone resorption in vitro by a WASP-peptide containing pTyr294 amino acid.
Dramatic inhibition of osteoclast sealing ring formation and bone resorption in vitro by a WASP-peptide containing pTyr294 amino acid.
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DOI：
10.1186/1750-2187-3-4
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发表时间：
2008-02-20
影响因子：
--
通讯作者：
Chellaiah, Meenakshi A
中科院分区：
文献类型：
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作者：
Ma, Tao;Samanna, Venkatesababa;Chellaiah, Meenakshi A
Wiskott Aldrich综合征蛋白（WASP）在破骨细胞的密封环形成和骨吸收中具有独特的调节作用。在这里，我们使用tat转导方法，展示了WASP结构域在密封圈形成和骨吸收中的可能作用。tat融合全长WASP肽的转导诱导Arp2/3复合物形成、f -肌动蛋白含量、密封环形成和骨吸收。含有碱性、维蜂蛋白中心、pTyr294和脯氨酸丰富区域的WASP肽的转导在不同程度上抑制了上述过程。含有碱性区、马尾草蛋白中心区和脯氨酸丰富区的WASP肽对骨的吸收能力降低，吸收面积与密封环的大小相当。然而，用含有pTyr294aa的WASP肽转导的破骨细胞表明：a) c-Src与内源性WASP的相互作用和磷酸化显著减少；B)密封圈结构完全丧失；C)外周边缘形成富含肌动蛋白的斑块，包含丝状突起；D)体外骨吸收能力降低。这些发现表明，调节pTyr294aa磷酸化状态有助于整合参与密封环组装的多种信号分子和途径。
Wiskott Aldrich Syndrome protein (WASP) has a unique regulatory role in sealing ring formation and bone resorption in osteoclasts. Here, using the TAT-transduction method, we show the possible role of WASP domain(s) in sealing ring formation and bone resorption. Transduction of TAT-fused full-length WASP peptide induced Arp2/3 complex formation, F-actin content, sealing ring formation and bone resorption. Transduction of WASP peptides containing basic, verpolin-central, pTyr294, and proline-rich regions inhibited the processes listed above at various levels. The ability to resorb bone by WASP peptides containing basic, verpolin-central, and proline-rich regions was reduced and the resorbed area matched the size of the sealing ring. However, osteoclasts transduced with WASP peptide containing pTyr294aa demonstrated the following: a) a considerable decrease in the interaction and phosphorylation of c-Src with endogenous WASP; b) total loss of sealing ring-like structures; c) formation of actin-rich patches at the peripheral edge that contains filopodia-like projections; d) reduced capacity for bone resorption in vitro. These findings suggest that modulation of phosphorylation state of pTyr294aa assists in integrating multiple signaling molecule and pathways that partake in the assembly of sealing ring.