Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells

Maruyama, Satoshi; Yamazaki, Manabu; Xu, Bin; Essa, Ahmed; Abé, Tatsuya; Babkair, Hamzah; Cheng, Jun; Yamamoto, Tadashi; Saku, Takashi

doi:10.1016/j.bbrc.2013.03.057

Cited by 28 publications

(19 citation statements)

References 35 publications

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“…Several ligands can bind to the extracellular region of PDPN to promote transformed cell migration and tumorigenesis [37–40]. Accordingly, this extracellular region can be targeted by reagents to inhibit tumor cell growth and motility [15, 25, 27, 28].…”

Section: Discussionmentioning

confidence: 99%

PKA and CDK5 can phosphorylate specific serines on the intracellular domain of podoplanin (PDPN) to inhibit cell motility

Krishnan

Retzbach

Ramirez

et al. 2015

Experimental Cell Research

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Podoplanin (PDPN) is a transmembrane glycoprotein that promotes tumor cell migration, invasion, and cancer metastasis. In fact, PDPN expression is induced in many types of cancer. Thus, PDPN has emerged as a functionally relevant cancer biomarker and chemotherapeutic target. PDPN contains 2 intracellular serine residues that are conserved between species ranging from mouse to humans. Recent studies indicate that protein kinase A (PKA) can phosphorylate PDPN in order to inhibit cell migration. However, the number and identification of specific residues phosphorylated by PKA have not been defined. In addition, roles of other kinases that may phosphorylate PDPN to control cell migration have not been investigated. We report here that cyclin dependent kinase 5 (CDK5) can phosphorylate PDPN in addition to PKA. Moreover, results from this study indicate that PKA and CDK5 cooperate to phosphorylate PDPN on both intracellular serine residues to decrease cell motility. These results provide new insight into PDPN phosphorylation dynamics and the role of PDPN in cell motility. Understanding novel mechanisms of PDPN intracellular signaling could assist with designing novel targeted chemotherapeutic agents and procedures.

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Section: Discussionmentioning

confidence: 99%

PKA and CDK5 can phosphorylate specific serines on the intracellular domain of podoplanin (PDPN) to inhibit cell motility

Krishnan

Retzbach

Ramirez

et al. 2015

Experimental Cell Research

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“…In vivo models of murine mammary adenocarcinoma expressing high levels HSPB1 in the cell surface displayed larger tumors when implanted in nude mice, also presenting increased lung metastatic rates [140]. HSPA9 was shown to be secreted by oral squamous carcinoma cells and interact with the adhesion molecule podoplanin, which is involved in cell growth and invasiveness [15]. …”

Section: Functions Of Extracellular Hsps In Cancermentioning

confidence: 99%

Unconventional Secretion of Heat Shock Proteins in Cancer

Santos

Martins

Hajj

2017

IJMS

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Heat shock proteins (HSPs) are abundant cellular proteins involved with protein homeostasis. They have both constitutive and inducible isoforms, whose expression levels are further increased by stress conditions, such as temperature elevation, reduced oxygen levels, infection, inflammation and exposure to toxic substances. In these situations, HSPs exert a pivotal role in offering protection, preventing cell death and promoting cell recovery. Although the majority of HSPs functions are exerted in the cytoplasm and organelles, several lines of evidence reveal that HSPs are able to induce cell responses in the extracellular milieu. HSPs do not possess secretion signal peptides, and their secretion was subject to widespread skepticism until the demonstration of the role of unconventional secretion forms such as exosomes. Secretion of HSPs may confer immune system modulation and be a cell-to-cell mediated form of increasing stress resistance. Thus, there is a wide potential for secreted HSPs in resistance of cancer therapy and in the development new therapeutic strategies.

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“…7 PDPN has been suggested to have a role in cell migration and invasion, through interactions with its binding partners, such as ezrin, 17 CD44, 18 and heat shock protein A9. 19 Those interactions have been shown to induce epithelialmesenchymal transition (EMT), 17 although the involvement of EMT has been a matter of argument. 20 Hence, the actual molecular function of PDPN in cancer cells has remained largely unknown.…”

mentioning

confidence: 99%

Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma

Tsuneki

Yamazaki

Maruyama

et al. 2013

Laboratory Investigation

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Podoplanin (PDPN), one of the representative mucin-like type-I transmembrane glycoproteins specific to lymphatic endothelial cells, is expressed in various cancers including squamous cell carcinoma (SCC). On the basis of our previous studies, we have developed the hypothesis that PDPN functions in association with the extracellular matrix (ECM) from the cell surface side. The aim of this study was to elucidate the molecular role of PDPN in terms of cell adhesion, proliferation, and migration in oral SCC cells. Forty-four surgical specimens of oral SCC were used for immunohistochemistry for PDPN, and the expression profiles were correlated with their clinicopathological properties. Using ZK-1, a human oral SCC cell system, and five other cell systems, we examined PDPN expression levels by immunofluorescence, western blotting, and real-time PCR. The effects of transient PDPN knockdown by siRNA in ZK-1 were determined for cellular functions in terms of cell proliferation, adhesion, migration, and invasion in association with CD44 and hyaluronan. Cases without PDPN-positive cells were histopathologically classified as less-differentiated SCC, and SCC cells without PDPN more frequently invaded lymphatics. Adhesive properties of ZK-1 were significantly inhibited by siRNA, and PDPN was shown to collaborate with CD44 in cell adhesion to tether SCC cells with hyaluronan-rich ECM of the narrow intercellular space as well as with the stromal ECM. There was no siRNA effect in migration. We have demonstrated the primary function of PDPN in cell adhesion to ECM, which is to secondarily promote oral SCC cell proliferation.Laboratory Investigation (2013) 93, 921-932;

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Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells

Cited by 28 publications

References 35 publications

PKA and CDK5 can phosphorylate specific serines on the intracellular domain of podoplanin (PDPN) to inhibit cell motility

PKA and CDK5 can phosphorylate specific serines on the intracellular domain of podoplanin (PDPN) to inhibit cell motility

Unconventional Secretion of Heat Shock Proteins in Cancer

Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma

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