Extracellular Heat Shock Protein 90 Signals through Subdomain II and the NPVY Motif of LRP-1 Receptor to Akt1 and Akt2: a Circuit Essential for Promoting Skin Cell Migration In Vitro and Wound Healing In Vivo

Abstract

cNormal cells secrete heat shock protein 90 alpha (Hsp90␣) in response to tissue injury. Tumor cells have managed to constitutively secrete Hsp90␣ during invasion and metastasis. The sole function of extracellular Hsp90␣ (eHsp90␣) is to promote cell motility, a critical event for both wound healing and tumor progression. The mechanism of promotility action by eHsp90␣, however, has remained elusive. A key issue is whether eHsp90␣ still acts as a chaperone outside the cells or is a new and bona fide signaling molecule. Here, we have provided evidence that eHsp90␣ utilizes a unique transmembrane signaling mechanism to promote cell motility and wound healing. First, subdomain II in the extracellular part of low-density lipoprotein receptor-related protein 1 (LRP-1) receives the eHsp90␣ signal. Then, the NPVY but not the NPTY motif in the cytoplasmic tail of LRP-1 connects eHsp90␣ signaling to serine 473 but not threonine 308 phosphorylation in Akt kinases. Individual knockdown of Akt1, Akt2, or Akt3 revealed the importance of Akt1 and Akt2 in eHsp90␣-induced cell motility. Akt gene rescue experiments suggest that Akt1 and Akt2 work in concert, rather than independently, to mediate eHsp90␣ promotility signaling. Finally, Akt1 and Akt2 knockout mice showed impaired wound healing that cannot be corrected by topical application with the eHsp90␣ protein.

Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: A distinct branch of PI3K signaling

“…The three isoforms of Akt have differential effects on migration in diverse cell types: each isoform can be either stimulatory or inhibitory depending on specific cellular contexts [118,[137][138][139][140][141][142][143][144]. As reviewed above, loss of PI(3,4)P2-specific phosphatase INPP4B led to increased migration capacity in breast cancer [22] and melanoma cells [44] in wound healing assays.…”

Differential profiles of gastrointestinal proteins interacting with peptidoglycans from Lactobacillus plantarum and Staphylococcus aureus

“…Stabilizes and transports diverse proteins involved in cell migration, wound healing, and metastasis (Hance et al, 2014;Tsen et al, 2013) Serum albumin Binds to bacterial cell wall components such as PGN, LTA and LPS for the modulation of immune cell activation (Gioannini et al, 2002) Lysozyme Hydrolyzes the glycosidic bonds of PGN between MurNAc and GlcNAc (Ibrahim et al, 2001;Vocadlo et al, 2001) Peptidoglycan recognition protein 1 Exhibits bactericidal effects through either the interaction with muramyl-peptides of PGN or the activation of the CssR-CssS system (Dziarski et al, 2012) Histone H2B…”

Hsp70/Hsp90 Organising Protein (Hop): Beyond Interactions with Chaperones and Prion Proteins

“…In this way, Hop appears to function like a classical cytokine, binding to a transmembrane receptor to induce cellular signalling cascades. A similar effect has been noted with extracellular chaperones like Hsp90, which are able to induce signalling from cellular receptors like LRP-1 (Tsen et al 2013). The studies on extracellular Hop are particularly interesting since nothing is known about the mechanism of export or the isoform specificity of extracellular Hop.…”