Transforming growth factor α (TGFα)-stimulated secretion of HSP90α:: Using the receptor LRF-1/CD91 to promote human skin cell migration against a TGFβ-rich environment during wound healing
Transforming growth factor α (TGFα)-stimulated secretion of HSP90α:: Using the receptor LRF-1/CD91 to promote human skin cell migration against a TGFβ-rich environment during wound healing
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DOI：
10.1128/mcb.01287-07
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发表时间：
2008-05-01
影响因子：
5.3
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Cheng, Chieh-Fang;Fan, Jianhua;Li, Wei
启动并随后维持表皮和真皮细胞迁移是皮肤伤口愈合的基本过程。这些事件通常在不愈合的伤口中中断，导致患者发病甚至死亡。目前可用的治疗方法不能令人满意。为了确定新的伤口愈合的目标，我们研究了分泌的分子从转化生长因子（TGF α）刺激的人角质细胞，其中含有强大的运动，但不促有丝分裂，活性。蛋白质纯化使我们能够确定热休克蛋白90 α（hsp 90 α）的因素完全负责角质形成细胞分泌的运动活性。TGF α引起快速的膜转位，随后通过细胞中的非常规外泌体途径分泌hsp 90 α。分泌的hsp 90 a通过表面受体LRP-1（LDL受体相关蛋白1）/CD 91促进表皮和真皮细胞迁移。促进活性存在于中间结构域加上hsp 90 α的带电序列中，但不依赖于ATP酶活性。中和hsp 90 α的细胞外功能阻断TGF α诱导的角质形成细胞迁移。最有趣的是，与典型生长因子的作用不同，hsp 90 α信号传导覆盖了TGF β的抑制，TGF β是皮肤伤口中真皮细胞迁移的丰富抑制剂。这一发现为真皮细胞如何迁移到伤口环境中以建立新的结缔组织和血管的问题提供了长期寻求的答案。因此，分泌的hsp 90 α是一种潜在的伤口愈合新试剂。
Jump-starting and subsequently maintaining epidermal and dermal cell migration are essential processes for skin wound healing. These events are often disrupted in nonhealing wounds, causing patient morbidity and even fatality. Currently available treatments are unsatisfactory. To identify novel wound-healing targets, we investigated secreted molecules from transforming growth factor a (TGF alpha)-stimulated human keratinoytes, which contained strong motogenic, but not mitogenic, activity. Protein purification allowed us to identify the heat shock protein 90 alpha (hsp90 alpha) as the factor fully responsible for the motogenic activity in keratinocyte secretion. TGFa causes rapid membrane translocation and subsequent secretion of hsp90 alpha via the unconventional exosome pathway in the cells. Secreted hsp90a promotes both epidermal and dermal cell migration through the surface receptor LRP-1 (LDL receptor-related protein 1)/CD91. The promotility activity resides in the middle domain plus the charged sequence of hsp90 alpha but is independent of the ATPase activity. Neutralizing the extracellular function of hsp90 alpha blocks TGF alpha-induced keratinicyte migration. Most intriguingly, unlike the effects of canonical growth factors, the hsp90 alpha signaling overrides the inhibition of TGF beta, an abundant inhibitor of dermal cell migration in skin wounds. This finding provides a long-sought answer to the question of how dermal cells migrate into the wound environment to build new connective tissues and blood vessels. Thus, secreted hsp90 alpha is potentially a new agent for wound healing.