Nuclear localization of ING3 is required to suppress melanoma cell migration, invasion and angiogenesis

Ruiyao Zhou1, Anand Rotte2, Gang Li2

  • 1Department of General Surgery, The Third Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Insights

The nuclear localization sequence (NLS) of the tumor suppressor ING3 was identified. ING3

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Inhibitor of growth family member 3 (ING3) is a tumor suppressor involved in cell cycle regulation, apoptosis, and transcription.
  • Nuclear ING3 has demonstrated significant biological functions, but its nuclear localization sequence (NLS) and specific roles remain undefined.

Purpose of the Study:

  • To identify the NLS of ING3.
  • To investigate the biological functions of ING3 nuclear localization in melanoma.

Main Methods:

  • Generation and analysis of various ING3 mutants to pinpoint the NLS.
  • Site-directed mutagenesis to create the ING3-K164A mutant.
  • Overexpression studies in melanoma cells to assess cellular localization and functional impact.

Main Results:

  • The NLS of ING3 was identified as the KKFK sequence between amino acids 164 and 167.
  • Mutation of Lysine 164 to Alanine (ING3-K164A) resulted in cytoplasmic retention of ING3.
  • Overexpression of wild-type ING3 inhibited melanoma cell migration, invasion, and angiogenesis, effects that were abolished by the ING3-K164A mutant.

Conclusions:

  • This study successfully identified the NLS of ING3, highlighting its critical role in nuclear transport.
  • Nuclear localization of ING3 is essential for its tumor-suppressive functions, including the inhibition of melanoma cell migration, invasion, and angiogenesis.
  • Further research is warranted to explore the post-translational modifications of ING3 at residue 164 and their impact on nuclear transport and cancer development.

Related Concept Videos

Nuclear Localization Signals and Import01:46

Nuclear Localization Signals and Import

Proteins targeted to the nucleus carry short stretches of amino acid sequences called the nuclear localization signal or NLS. Classical nuclear localization signals are of two types: monopartite and bipartite NLS. Monopartite classical NLS (cNLS) consists of a single cluster of 4-8 amino acids. Bipartite cNLS consists of two clusters of  2-3 amino acids and a 9-12 residue long proline-rich linker bridging the two clusters. Signal clusters are rich in positively charged amino acids such as...
7.4K
Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
3.1K
Nuclear Protein Sorting01:34

Nuclear Protein Sorting

Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
6.1K
Cancer Cell Migration through Invadopodia01:35

Cancer Cell Migration through Invadopodia

Invadosome is a broad category of cell surface structures with proteolytic activity that  degrades the extracellular matrix (ECM). Invadosomes are present in normal cell types, including macrophages, endothelial cells, and neurons, as well as tumor cells. Although the macrophage podosomes and tumor cell invadopodia are classified as invadosomes, they have different structures, molecular pathways, and functions. Podosomes are short structures that last for a few minutes. However,...
3.1K
Directionality of Nuclear Transport01:42

Directionality of Nuclear Transport

Ras-related nuclear protein or Ran is a small G protein that cycles between its GTP and GDP bound states. Ran specific regulators, a Ran GTPase Activating Protein or RanGAP present in the cytosol and a Ran guanine nucleotide exchange factor or RanGEF present inside the nucleus regulate GTP/GDP exchange. A high concentration of GTP inside the cells, in addition to this asymmetric distribution of  Ran-specific regulators, leads to a higher RanGTP concentration inside the nucleus. This...
4.4K