Acetylation and activation of STAT3 mediated by nuclear translocation of CD44

Lee, Jia-Lin; Wang, Mei-Jung; Chen, Jeou-Yuan

doi:10.1083/jcb.200812060

Cited by 139 publications

(124 citation statements)

References 28 publications

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“…We also show that mutant CD44, lacking the signal peptide required for membrane localization, has a diminished ability to localize to the nucleus. Ligation of CD44 by osteopontin or Hermes-3 antibody promotes its nuclear localization (22). We show here that hyaluronic acid binding does not influence nuclear localization, as nuclear import of the R41A mutant is not impaired.…”

Section: Discussionmentioning

confidence: 59%

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Transportin Regulates Nuclear Import of CD44

Janiszewska

Vito

Bitoux

et al. 2010

Journal of Biological Chemistry

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CD44 is a facultative cell surface proteoglycan that serves as the principal cell surface receptor for hyaluronan (HA). Studies have shown that in addition to participating in numerous signaling pathways, CD44 becomes internalized upon engagement by ligand and that a portion of its intracellular domain can translocate to the nucleus where it is believed to play a functional role in cell proliferation and survival. However, the mechanisms whereby fragments of CD44 enter the nucleus have not been elucidated. Here we show that CD44 interacts with two import receptors of the importin ␤ superfamily, importin ␤ itself and transportin. Inhibition of importin ␤-dependent transport failed to block CD44 accumulation in the nucleus. By contrast, inhibition of the transportin-dependent pathway abrogated CD44 import. Mutagenesis of the intracellular domain of CD44 revealed that the 20 membrane-proximal residues contain sequences required for transportin-mediated nuclear transport. Our observations provide evidence that CD44 interacts with importin family members and identify the transportin-dependent pathway as the mechanism whereby full-length CD44 enters the nucleus.Proteins cross the double membrane of the nuclear envelope through nuclear pores. To traverse this barrier, proteins larger than 40 kDa must bind to soluble transport factors or carrier molecules that shuttle between the cytoplasm and the nucleus (1). Most of the nuclear transport factors belong to the ␤-karyopherin family and are classified, according to their function, as importins or exportins (2). In the cytoplasm, cargo proteins containing a nuclear localization signal (NLS) 2 are usually bound by the adaptor protein importin ␣, followed by the carrier importin ␤ (2), although in some cases, importin ␣ binding is not required (3). Importin-bound cargo is then translocated through the nuclear pore complex and is released in the nucleus following binding of importin ␤ to RanGTP protein (2). The importin-Ran complex is exported to the cytoplasm where it dissociates upon RanGTP conversion to RanGDP. An analogous mechanism is used by mRNA-binding proteins, where cargo is recognized by the transportin1 carrier (2). Interestingly, it has also been shown that some proteins, including ␤-catenin, SMAD, and ERK2, can be imported into the nucleus without involvement of importins and RanGTP (4).Nuclear export is analogous to the import mechanism. There is a single karyopherin protein, Crm1, that upon recognition of a nuclear export sequence binds the target protein in the nucleus and upon stimulation by Ran protein releases the cargo into the cytoplasm (2). The mechanisms described above are common for cytoplasmic proteins, but there is also some evidence that the same pathways might be used for nuclear translocation of the full-length transmembrane receptors (5, 6).Growth factor receptor signaling proceeds as a cascade of intracellular events. Receptor engagement by ligand on the cell surface typically results in receptor clustering and, depending on the receptor type...

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Section: Discussionmentioning

confidence: 59%

“…Previous work (22) has shown that ligation of cell surface CD44 by antibody or osteopontin can enhance its nuclear translocation. We therefore asked whether hyaluronic acid binding could play the same role in vivo.…”

Section: Resultsmentioning

confidence: 99%

Transportin Regulates Nuclear Import of CD44

Janiszewska

Vito

Bitoux

et al. 2010

Journal of Biological Chemistry

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“…In non-small cell lung cancer, hyaluronan promotes the CD44-dependent association of the stem cell marker NANOG with both the phosphorylated and the unphosphorylated forms of STAT3, resulting in chemo-resistance that depends upon induced expression of the microRNA miR-21 (28). Lee et al (19) have demonstrated that the transmembrane glycoprotein CD44, recently recognized to be a signature of cancer stem cells, is internalized following its binding to osteopontin or Hermes 3, an anti-CD44 antibody. In the nucleus, CD44, in complex with STAT3 and p300, activates the CCND1 promoter, thus stimulating cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Critical Role for Lysine 685 in Gene Expression Mediated by Transcription Factor Unphosphorylated STAT3

Dasgupta

Ünal

Willard

et al. 2014

Journal of Biological Chemistry

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Background: Lysine acetylation is an important regulatory modification of STAT3. Results: Acetylation of Lys-685 is critical for gene expression driven by unphosphorylated STAT3 (U-STAT3) but not by STAT3 phosphorylated on Tyr-705 (Y-P-STAT3). Conclusion: Distinct modifications regulate U-STAT3 and Y-P-STAT3 differentially. Significance: Lys-685 acetylation could be targeted to block U-STAT3-specific functions, such as activation of oncogene expression.

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“…Treatment with resveratrol (a histone deacetylase activator) significantly decreases the STAT3 K685 acetylation followed by increase in ERα expression at both protein and mRNA level as well as sensitizes the TNBC cells to tamoxifen-induced cell death [43]. Acetylated K685 STAT3 is also known to interact with CD44 and regulate transcription of cyclin D1 gene in case of gastric cancer [81]. Acetylated STAT3 is also known to regulate the non-canonical NF-κB signaling pathway.…”

Section: Ps727 Phosphorylation and K685 Acetylation Of Stat3: The Nonmentioning

confidence: 99%

Approaching non-canonical STAT3 signaling to redefine cancer therapeutic strategy

Dimri¹,

Sukanya²,

De³

2017

Integr Mol Med

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STAT3 is an essential cellular transcription factor that activates a cascade of survival and proliferation signaling program in cells upon cytokine and growth factor stimulus. STAT3 forms a converging point for many upstream activated signaling pathways required for maintaining normal and oncogenic condition. As an active transcription factor, it controls transcription of downstream genes involved in various steps of cancer progression like cell proliferation, migration, immune evasion and angiogenesis. It is known to be constitutively active in many cancers with approximately 40% of breast cancer cases positive for activated STAT3. Apart from the wellstudied pY705 activation (canonical pathway), STAT3 is reported to undergo alternative post-translational modifications like pS727 and K685Ac (non-canonical pathway) that are now appearing to be responsible for triggering activated STAT3 in many cancers including breast cancer. Hence, correct designation and targeting ability of these post-translational modifications (PTM) of STAT3 signaling in any particular cancer may hold the key in treating patients with STAT3 overexpression.

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Acetylation and activation of STAT3 mediated by nuclear translocation of CD44

Cited by 139 publications

References 28 publications

Transportin Regulates Nuclear Import of CD44

Transportin Regulates Nuclear Import of CD44

Critical Role for Lysine 685 in Gene Expression Mediated by Transcription Factor Unphosphorylated STAT3

Approaching non-canonical STAT3 signaling to redefine cancer therapeutic strategy

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