Aside from Polo and Aurora, a third but less studied kinase family involved in mitosis regulation is the never in mitosis-gene A(NIMA)-related kinases(Neks). The founding member of this family is the sole member NIMA ...Aside from Polo and Aurora, a third but less studied kinase family involved in mitosis regulation is the never in mitosis-gene A(NIMA)-related kinases(Neks). The founding member of this family is the sole member NIMA of Aspergillus nidulans, which is crucial for the initiation of mitosis in that organism. All 11 human Neks have been functionally assigned to one of the three core functions established for this family in mammals:(1) centrioles/mitosis;(2) primary ciliary function/ciliopathies; and(3) DNA damage response(DDR). Recent findings, especially on Nek 1 and 8, showed however, that several Neks participate in parallel in at least two of these contexts: primary ciliary function and DDR. In the core section of this in-depth review, we report the current detailed functional knowledge on each of the 11 Neks. In the discussion, we return to the cross-connections among Neks and point out how our and other groups' functional and interactomics studies revealed that most Neks interact with protein partners associated with two if not all three of the functional contexts. We then raise the hypothesis that Neks may be the connecting regulatory elements that allow the cell to fine tune and synchronize the cellular events associated with these three core functions. The new and exciting findings on the Nek family open new perspectives and should allow the Neks to finally claim the attention they deserve in the field of kinases and cell cycle biology.展开更多
Delivery of therapeutic peptides or proteins into tissues is severely limited by the size and biochemical properties of the molecules. Protein transduction domain (PTD)-mediated cargo transduction represents a novel a...Delivery of therapeutic peptides or proteins into tissues is severely limited by the size and biochemical properties of the molecules. Protein transduction domain (PTD)-mediated cargo transduction represents a novel and promising strategy to deliver biologically active peptides in vivo. The first PTD was identified from the HIV-1 transactivating transcriptional activator protein Tat in 1988. Since then, other PTDs have also been identified, including the third α-helix of the antennapedia homeotic transcription factor and synthetic peptide carriers. However, Tat PTD (amino acids 47 - 57) has shown markedly better ability for intracellular delivery than other PTDs. It has been demonstrated that fusion peptides containing the Tat PTD enter the central nervous system after systemic administration. Our previous study has shown that i.p. injected Tat-PSD-95 PDZ2 expresses in the central nervous system and significantly disrupts PDZ domain-mediated protein interactions between PSD-95 and N-methyl-D-aspartate receptor subunit NR2A/2B, thereby alleviating chronic pain. Therefore, Tat-mediated intracellular delivery can be used for systemic administration of analgesics in pain management.展开更多
基金Supported by Fundao de AmparoàPesquisa do Estado S o Paulo(FAPESP,Grant No.2010/51730-0)Conselho Nacional de Pesquisa e Desenvolvimento(CNPq)Centro Nacional de Pesquisa em Energia e Materiais(CNPEM)
文摘Aside from Polo and Aurora, a third but less studied kinase family involved in mitosis regulation is the never in mitosis-gene A(NIMA)-related kinases(Neks). The founding member of this family is the sole member NIMA of Aspergillus nidulans, which is crucial for the initiation of mitosis in that organism. All 11 human Neks have been functionally assigned to one of the three core functions established for this family in mammals:(1) centrioles/mitosis;(2) primary ciliary function/ciliopathies; and(3) DNA damage response(DDR). Recent findings, especially on Nek 1 and 8, showed however, that several Neks participate in parallel in at least two of these contexts: primary ciliary function and DDR. In the core section of this in-depth review, we report the current detailed functional knowledge on each of the 11 Neks. In the discussion, we return to the cross-connections among Neks and point out how our and other groups' functional and interactomics studies revealed that most Neks interact with protein partners associated with two if not all three of the functional contexts. We then raise the hypothesis that Neks may be the connecting regulatory elements that allow the cell to fine tune and synchronize the cellular events associated with these three core functions. The new and exciting findings on the Nek family open new perspectives and should allow the Neks to finally claim the attention they deserve in the field of kinases and cell cycle biology.
文摘Delivery of therapeutic peptides or proteins into tissues is severely limited by the size and biochemical properties of the molecules. Protein transduction domain (PTD)-mediated cargo transduction represents a novel and promising strategy to deliver biologically active peptides in vivo. The first PTD was identified from the HIV-1 transactivating transcriptional activator protein Tat in 1988. Since then, other PTDs have also been identified, including the third α-helix of the antennapedia homeotic transcription factor and synthetic peptide carriers. However, Tat PTD (amino acids 47 - 57) has shown markedly better ability for intracellular delivery than other PTDs. It has been demonstrated that fusion peptides containing the Tat PTD enter the central nervous system after systemic administration. Our previous study has shown that i.p. injected Tat-PSD-95 PDZ2 expresses in the central nervous system and significantly disrupts PDZ domain-mediated protein interactions between PSD-95 and N-methyl-D-aspartate receptor subunit NR2A/2B, thereby alleviating chronic pain. Therefore, Tat-mediated intracellular delivery can be used for systemic administration of analgesics in pain management.
