Labour MP Tristram Hunt is quitting as an MP to become the director of London's Victoria and Albert Museum, triggering a by-election.
Mr Hunt told the BBC that while he had "had differences" with party leader Jeremy Corbyn in the past "that wasn't the spur" for stepping down.
"The spur was the incredible opportunity of the job," he said.
Labour leader Mr Corbyn said he wished him well and was confident Labour would hold the Stoke-on-Trent Central seat.
Asked if he was secretly pleased that an MP who has been critical of his leadership was going, Mr Corbyn said: "No, I don't want anyone to resign, I don't want to lose MPs but he has taken this position as director of the V&A, good luck to him."
He said he was confident of winning the by-election: "It's been a Labour seat for a long time, we have a strong message to put out .. I'm looking forward to the campaign."
Mr Hunt is the second Labour MP in a matter of weeks to quit Parliament for a job outside politics. Jamie Reed announced last month he was standing down as MP for Copeland to take up a post at the Sellafield nuclear plant.
Mr Hunt's departure sets up another potentially awkward by-election for Mr Corbyn, in a traditionally safe Labour seat where UKIP made a strong showing in the last general election. The seat is set to be abolished under new boundary proposals.
Labour grandee Lord Mandelson said he believed Mr Hunt quit politics because he was "unhappy", like "many other MPs" over Labour's electoral chances.
"The prospects of us winning a national general election will remain distant the longer Jeremy Corbyn and his ramshackle outfit remain in charge of the party's fortunes," he told the BBC's Week in Westminster.
In a letter to local party members explaining his decision, Mr Hunt said: "I am sorry to put you, the party and the people of Stoke-on-Trent, through a by-election. I have no desire to rock the boat now and anyone who interprets my decision to leave in that way is just plain wrong."
The former TV historian was elected to represent Stoke-on-Trent in 2010 and was re-elected in 2015 with a majority of 5,179. UKIP came second.
He refused to serve in the shadow cabinet following Mr Corbyn's leadership victory in September 2015. He also argued that the Labour leader should have done more to persuade its voters to back the Remain campaign during last year's EU referendum.
By Ben Wright, BBC political correspondent
Tristram Hunt's resignation follows that of Jamie Reed last month - another Labour MP who had been critical of the party's shift to the left - and it leaves Mr Corbyn facing another difficult by-election that UKIP will be fighting to win.
I don't think Jeremy Corbyn will mind in the slightest that Tristram Hunt has gone. But Mr Corbyn's critics in Parliament face a dilemma: to follow Tristram Hunt out of politics or to stay and fight for a party they believe is in deep trouble.
Labour deputy leader Tom Watson said he was "disappointed to see a talented MP like Tristram step down".
Conservative former chancellor George Osborne commented: "@TristramHuntMP is a brilliant, bold choice by @V_and_A. I suspect it'll be a while before we see another Labour MP called Tristram."
Liberal Democrat president Baroness Brinton said Mr Hunt's resignation was "a sign of how Labour are ripping themselves apart". "What is worrying is when first Jamie Reed and now Tristram Hunt decide they can achieve more positive change outside, rather than inside Parliament," she said.
Former UKIP leader Nigel Farage tweeted: "Tristram Hunt's resignation from Stoke will be followed by many others. Labour is doomed."
The V&A said Mr Hunt would bring "widespread expertise" to the museum.
Chairman Nicholas Coleridge said: "He has a highly compelling mixture of experience across public life, the arts, history, education and academia, and knows our collections well from his writing and broadcasting. "
"In addition, he is an informed and articulate leader and communicator on numerous facets of culture, both historic and contemporary."
Mr Hunt, whose V&A appointment was signed off by Prime Minister Theresa May and Culture Secretary Karen Bradley, succeeds Martin Roth, who saw attendances triple during his five-year period in charge. One of Mr Hunt's first tasks will be overseeing the development of V&A outposts in places such as Dundee.
Mr Roth earned a salary of £145,000-£150,000 as part of a total package worth £225,000-£230,000 in 2015/16 - well above Mr Hunt's current salary of £74,962 as an MP.