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F-box protein substrate recognition: a new insight.

Chen BB, Mallampalli RK - Cell Cycle (2012)

View Article: PubMed Central - PubMed

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Both cyclin D2 and cyclin D3 harbor canonical IQ motifs typical of calcium-independent CaM binding proteins... Within the IQ motif, it appears that the glutamine residue is essential for Fbxl2 targeting as cyclin D2 and cyclin D3 variants harboring glutamine substitutions within the IQ motif exhibit significantly extended half-lives in vivo... Interestingly, threonine, within cyclin D1, is recognized by the F-box proteins Fbxo4, Fbxw8 and Fbxo31 to facilitate its ubiquitination... Although this threonine site is highly conserved among the D cyclins, Fbxl2 did not utilize this molecular signal for targeting, but rather docks within a consensus IQ signature within these cyclins to facilitate their ubiquitination... The intermolecular competition between SCF complex and CaM regulate other proteins involved in mitotic progression... However, these activities are opposed by Fbxl2, which again engages CaM for access to Aurora B within a shared IQ motif... More recent studies reveal that the SCF complex might also play an important role in regulating the NFκB pathway and cytokine responses... Fbxl2 acts as a crucial, pan-reactive inhibitor of tumor necrosis factor receptor-associated factors (TRAF) function by mediating their polyubiquitination... Interestingly, TRAF proteins contain a conserved 1–10 CaM-binding motif in which a tryptophan residue is essential for Fbxl2 targeting... In conclusion, studies in our laboratory have identified multiple substrates of Fbxl2, all of which are CaM-binding proteins and are essential for either cell proliferative activity or innate immunity... The ability of Fbxl2 to recognize a CaM binding signature appears to represent a unique molecular mechanism of F box protein substrate targeting that underlies its ability to exhibit tumorocidal activity and possibly play a role in immune suppression... Indeed, Fbxl2 expression is significantly reduced in peripheral blood cells from leukemic subjects, where its substrates cyclin D3, cyclin D2, Aurora B are highly expressed.

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Figure 1. SCFFbxl2 complex targets many substrates for ubiquitination and it is antagonized by CaM.
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Figure 1: Figure 1. SCFFbxl2 complex targets many substrates for ubiquitination and it is antagonized by CaM.

Mentions: More recent studies reveal that the SCFFbxl2 complex might also play an important role in regulating the NFκB pathway and cytokine responses. Fbxl2 acts as a crucial, pan-reactive inhibitor of tumor necrosis factor receptor-associated factors (TRAF) function by mediating their polyubiquitination.10 By eliminating TRAFs, Fbxl2 inhibits NFκB activity and secretion of a broad spectrum of Th1 panel cytokines. Interestingly, TRAF proteins contain a conserved 1–10 CaM-binding motif in which a tryptophan residue is essential for Fbxl2 targeting.10 In conclusion, studies in our laboratory have identified multiple substrates of Fbxl2, all of which are CaM-binding proteins and are essential for either cell proliferative activity or innate immunity. The ability of Fbxl2 to recognize a CaM binding signature appears to represent a unique molecular mechanism of F box protein substrate targeting that underlies its ability to exhibit tumorocidal activity and possibly play a role in immune suppression. Indeed, Fbxl2 expression is significantly reduced in peripheral blood cells from leukemic subjects, where its substrates cyclin D3, cyclin D2, Aurora B are highly expressed.6 Additional investigations are needed to assess the expression of Fbxl2 in subjects with inflammatory illness, such as sepsis and pneumonia. (Fig. 1)


F-box protein substrate recognition: a new insight.

Chen BB, Mallampalli RK - Cell Cycle (2012)

Figure 1. SCFFbxl2 complex targets many substrates for ubiquitination and it is antagonized by CaM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3646851&req=5

Figure 1: Figure 1. SCFFbxl2 complex targets many substrates for ubiquitination and it is antagonized by CaM.
Mentions: More recent studies reveal that the SCFFbxl2 complex might also play an important role in regulating the NFκB pathway and cytokine responses. Fbxl2 acts as a crucial, pan-reactive inhibitor of tumor necrosis factor receptor-associated factors (TRAF) function by mediating their polyubiquitination.10 By eliminating TRAFs, Fbxl2 inhibits NFκB activity and secretion of a broad spectrum of Th1 panel cytokines. Interestingly, TRAF proteins contain a conserved 1–10 CaM-binding motif in which a tryptophan residue is essential for Fbxl2 targeting.10 In conclusion, studies in our laboratory have identified multiple substrates of Fbxl2, all of which are CaM-binding proteins and are essential for either cell proliferative activity or innate immunity. The ability of Fbxl2 to recognize a CaM binding signature appears to represent a unique molecular mechanism of F box protein substrate targeting that underlies its ability to exhibit tumorocidal activity and possibly play a role in immune suppression. Indeed, Fbxl2 expression is significantly reduced in peripheral blood cells from leukemic subjects, where its substrates cyclin D3, cyclin D2, Aurora B are highly expressed.6 Additional investigations are needed to assess the expression of Fbxl2 in subjects with inflammatory illness, such as sepsis and pneumonia. (Fig. 1)

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Both cyclin D2 and cyclin D3 harbor canonical IQ motifs typical of calcium-independent CaM binding proteins... Within the IQ motif, it appears that the glutamine residue is essential for Fbxl2 targeting as cyclin D2 and cyclin D3 variants harboring glutamine substitutions within the IQ motif exhibit significantly extended half-lives in vivo... Interestingly, threonine, within cyclin D1, is recognized by the F-box proteins Fbxo4, Fbxw8 and Fbxo31 to facilitate its ubiquitination... Although this threonine site is highly conserved among the D cyclins, Fbxl2 did not utilize this molecular signal for targeting, but rather docks within a consensus IQ signature within these cyclins to facilitate their ubiquitination... The intermolecular competition between SCF complex and CaM regulate other proteins involved in mitotic progression... However, these activities are opposed by Fbxl2, which again engages CaM for access to Aurora B within a shared IQ motif... More recent studies reveal that the SCF complex might also play an important role in regulating the NFκB pathway and cytokine responses... Fbxl2 acts as a crucial, pan-reactive inhibitor of tumor necrosis factor receptor-associated factors (TRAF) function by mediating their polyubiquitination... Interestingly, TRAF proteins contain a conserved 1–10 CaM-binding motif in which a tryptophan residue is essential for Fbxl2 targeting... In conclusion, studies in our laboratory have identified multiple substrates of Fbxl2, all of which are CaM-binding proteins and are essential for either cell proliferative activity or innate immunity... The ability of Fbxl2 to recognize a CaM binding signature appears to represent a unique molecular mechanism of F box protein substrate targeting that underlies its ability to exhibit tumorocidal activity and possibly play a role in immune suppression... Indeed, Fbxl2 expression is significantly reduced in peripheral blood cells from leukemic subjects, where its substrates cyclin D3, cyclin D2, Aurora B are highly expressed.

Show MeSH