A new family of heparin-binding factors: Strong conservation of midkine (MK) sequences between the human and the mouse

Tsutsui, Jun-ichiro; Uehara, Kazuyoshi; Kadomatsu, Kenji; Matsubara, Shigeo; Muramatsu, Takashi

doi:10.1016/s0006-291x(05)80255-4

Cited by 121 publications

(76 citation statements)

References 22 publications

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“…In particular, we focus on the expression, distribution, and function of MK in the tumors of NF1. The 13 kD heparin binding, secreted MK shows 45% amino acid homology, complete conservation of all ten cysteine residues and of the putative heparin binding site to the only other protein family member pleiotrophin (PTN) (Kretschmer et al, 1991;Tsutsui et al, 1991). MK and PTN are highly conserved during evolution and their rigid three dimensional structure predicts two domains with perhaps distinct function (Iwasaki et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells

et al. 2001

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Section: Introductionmentioning

confidence: 99%

The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells

et al. 2001

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“…coli is also devoid of mitogenic activity MK was found as the product of a gene that is expressed at the initial stage of retinoic acid- (23). In human tumors, MK is more strongly expressed than HB-GAM/PTN (49). In all of 6 surgically removed Wilms' tumor examined, MK mRNA was found to be strongly expressed, whereas normal human renal tissue expresses only a low level of MK mRNA.…”

Section: Other Activitiesmentioning

confidence: 91%

The Midkine Family of Growth/ Differentiation Factors

Muramatsu

1994

Dev Growth Differ

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“…Plasmid Constructs and Transfection-Human MK consists of 143 amino acids (32). Signal sequence-containing full-length (SSFL, 1-143 aa) and signal sequence-containing C-terminal half-deletion mutant (SS⌬C, 1-81 aa) were designed.…”

Section: Methodsmentioning

confidence: 99%

“…The N-terminal half-domain corresponds to Lys 23 -Gly 81 , and the C-terminal half-domain corresponds to Ala 82 -Asp 143 of human MK (32). To determine the domain responsible for nuclear localization, we constructed expression vectors corresponding to these domains.…”

Section: Fig 1 Lysosome-and Proteasome-dependent Degradation Of Intmentioning

confidence: 99%

Proteasomal Degradation of the Nuclear Targeting Growth Factor Midkine

Suzuki

Shibata

Urano

et al. 2004

Journal of Biological Chemistry

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It is widely held that growth factor signaling is terminated by lysosomal degradation of its activated receptor and the endocytosed growth factor is transported to lysosomes. Nuclear targeting is another important pathway through which signals of growth factors are mediated. However, mechanisms underlying desensitization of nuclear targeting growth factors are poorly understood. Here we report that the nuclear targeting pathway is down-regulated by the proteasome system. Degradation of endocytosed midkine, a heparin-binding growth factor, was suppressed by both proteasome and lysosome inhibitors to similar extents. By contrast, a proteasome inhibitor, but not lysosome ones, accelerated the nuclear accumulation of midkine. An expression vector of signal sequence-less midkine, which is produced in the cytosol, was constructed because endocytosed midkine may be translocated to the cytosol from cellular compartments before entering the nucleus. The cytosol-produced midkine underwent proteasomal degradation and accumulated in the nucleus as did the endocytosed midkine. It was polyubiquitinated, and its nuclear accumulation was enhanced by a proteasome inhibitor. We further dissected the midkine molecule to investigate roles in degradation and trafficking. The Nterminal half-domain of midkine was significantly more susceptible to proteasomal degradation, whereas the Cterminal half-domain was sufficient for nuclear localization. Together, these data highlight the desensitization of nuclear targeting by growth factors and indicate a critical role of the proteasome system in it.Coordinated regulation of "on" and "off" of signaling is essential for life. Upon ligation of a growth factor with its receptor(s), receptor-mediated intracellular signaling starts from the cell surface and/or endosomes. Desensitization (termination of signaling) then takes place via degradation of the activated receptor. Degradation of the activated receptor occurs essentially through the following two mechanisms. First, the intracellular domain of the activated receptor is degraded by the proteasome system as revealed for the ␤c chain, a shared receptor for interleukin-5 and -3 and granulocyte-macrophage colony-stimulating factor (1). Second, endocytosed receptors are transported from endosomes to lysosomes where they are degraded.Because the proteasome system plays a critical role in endosome-to-lysosome trafficking (1-7), it may indirectly regulate the lysosomal degradation of receptors. In addition to the classical desensitization described above, an additional route, namely nuclear targeting by growth factors, should be considered. In this case, signaling is mediated directly by the growth factor and not via the cell surface receptor. Therefore, desensitization occurs only when the growth factor is degraded.Mounting evidence indicates that nuclear targeting by growth factors plays an indispensable role in their biological activities. For example, the nuclear localization of fibroblast growth factor 1 and Schwannoma-derived growth factor is n...

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A new family of heparin-binding factors: Strong conservation of midkine (MK) sequences between the human and the mouse

Cited by 121 publications

References 22 publications

The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells

The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells

The Midkine Family of Growth/ Differentiation Factors

Proteasomal Degradation of the Nuclear Targeting Growth Factor Midkine

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