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I am reading about cyclins, cdks and Rb (Retinoblastoma) and some of the terminology is not clear to me.

I understand that when CDK phosphorylates Rb, it disconnects from E2F, and E2F can act as a transcription factor. My question is about the terminology.

My questions are:

  1. When people say "Rb is active", do they mean "active = phosphorylated state" (where E2F is free from Rb) or do they mean "active = not phosphorylated state"?

  2. Does "active cyclin" means cyclin is going to join CDK and cell cycle proceeds? or is "active cyclin = cyclin is not activating CDK and cell cycle paused"?

  3. Active CDK means CDK is activated by cyclin and cell cycle can proceed?

In general, Maybe one can say that binding (Rb with E2F or Cyclin with CKD) means activation and disconnecting means inactivation?

Thanks!

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(Image source: Kolch, Walter, et al. "The role of Raf kinases in malignant transformation." Expert reviews in molecular medicine 4.8 (2002): 1-18.)

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  1. The terminology of "Rb is active/inactive" refers to the activity of inhibiting E2F. So active Rb inhibits E2F, while inactive Rb doesn't inhibit E2F.

    With regard to Rb and phosphorylation - the story seems to be more complex ([1] describes Rb as an enigma).
    According to [2] (this quote is from the summary of the paper by eLife):

    Narasimha, Kaulich, Shapiro et al. now present biochemical analyses of Rb proteins that show— completely unexpectedly—that the cyclin D complex adds just one phosphate group to Rb during the G1 phase, although this group can be added to one of fourteen different sites. The resulting 'mono-phosphorylated' Rb varieties can each sequester different transcription factors and stop them working.
    At the restriction point, many more phosphate groups are then rapidly added, and the Rb protein is inactivated by a different cyclin. This cyclin—called Cyclin E—then drives cells into the next phase of the cell cycle. Establishing how cyclin E is activated is a priority for future research.

  2. + 3. Wikipedia's Cyclin-dependent kinase (CDK) page says:

    By definition, a CDK binds a regulatory protein called a cyclin. Without cyclin, CDK has little kinase activity; only the cyclin-CDK complex is an active kinase.

    Wikipedia's Protein kinase page says:

    A protein kinase is a kinase enzyme that modifies other molecules, mostly proteins, by chemically adding phosphate groups to them (phosphorylation).

    And here is a nice visual explanation from Life: The Science of Biology (10th edition):

    CDK

    So both "active CDK" and "active cyclin-CDK complex" (and according to the other answer, also "active cyclin") refer to the case in which a cyclin is bound to a CDK to form a cyclin-CDK complex, such that the CDK might phosphorylate some substrate.
    (I didn't mention the cell cycle here on purpose, as I am not an expert, and so I am wary of claiming that an active CDK always pushes the cell cycle forward. If I understand correctly, we still don't know exactly how each cyclin-CDK complex affects the cell cycle.)


As for your last question:

In general, Maybe one can say that binding (Rb with E2F or Cyclin with CKD) means activation and disconnecting means inactivation?

As mentioned above, you could say that about a cyclin and its CDK.
Unfortunately, you can't say that in general. E2F here is a counter example (it is inhibited when Rb binds to it and activated when Rb disconnects from it).
However, you could say that in general, when something binds to a protein, the protein might change its shape, which might lead to activating or inhibiting some function.



[1] Dyson, Nicholas J. "RB1: a prototype tumor suppressor and an enigma." Genes & development 30.13 (2016): 1492-1502.

[2] Narasimha, Anil M., et al. "Cyclin D activates the Rb tumor suppressor by mono-phosphorylation." Elife 3 (2014): e02872.

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Rb: The underphosphorylated, active form of RB1 interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest. (UniProt: P06400)

Cyclin-D: Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G1/S transition. (UniProt: P24385)

Active cyclin-D (i.e., cyclin-D in complex with CDK4) phosporylates (i.e., inactivates) Rb.

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  • $\begingroup$ This answer makes complete sense to me and probably most folks who answer questions here, but given OP's confusion it might be helpful to explain a bit further and state very explicitly what's going on. $\endgroup$ – Bryan Krause Jun 22 '18 at 16:10

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